86 results on '"McKinzie DL"'
Search Results
2. Further Characterization of Multi-Organ DEARE and Protection by 16,16 Dimethyl Prostaglandin E2 in a Mouse Model of the Hematopoietic Acute Radiation Syndrome.
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Wu T, Pelus LM, Plett PA, Sampson CH, Chua HL, Fisher A, Feng H, Liu L, Li H, Ortiz M, Chittajallu S, Luo Q, Bhatwadekar AD, Meyer TB, Zhang X, Zhou D, Fischer KD, McKinzie DL, Miller SJ, and Orschell CM
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- Female, Male, Animals, Mice, Dinoprostone pharmacology, Bone Marrow radiation effects, Disease Models, Animal, Inflammation pathology, Whole-Body Irradiation adverse effects, Mice, Inbred C57BL, Acute Radiation Syndrome drug therapy, Acute Radiation Syndrome prevention & control, Acute Radiation Syndrome etiology, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Survivors of acute radiation exposure suffer from the delayed effects of acute radiation exposure (DEARE), a chronic condition affecting multiple organs, including lung, kidney, heart, gastrointestinal tract, eyes, and brain, and often causing cancer. While effective medical countermeasures (MCM) for the hematopoietic-acute radiation syndrome (H-ARS) have been identified and approved by the FDA, development of MCM for DEARE has not yet been successful. We previously documented residual bone marrow damage (RBMD) and progressive renal and cardiovascular DEARE in murine survivors of H-ARS, and significant survival efficacy of 16,16-dimethyl prostaglandin E2 (dmPGE2) given as a radioprotectant or radiomitigator for H-ARS. We now describe additional DEARE (physiological and neural function, progressive fur graying, ocular inflammation, and malignancy) developing after sub-threshold doses in our H-ARS model, and detailed analysis of the effects of dmPGE2 administered before (PGE-pre) or after (PGE-post) lethal total-body irradiation (TBI) on these DEARE. Administration of PGE-pre normalized the twofold reduction of white blood cells (WBC) and lymphocytes seen in vehicle-treated survivors (Veh), and increased the number of bone marrow (BM) cells, splenocytes, thymocytes, and phenotypically defined hematopoietic progenitor cells (HPC) and hematopoietic stem cells (HSC) to levels equivalent to those in non-irradiated age-matched controls. PGE-pre significantly protected HPC colony formation ex vivo by >twofold, long term-HSC in vivo engraftment potential up to ninefold, and significantly blunted TBI-induced myeloid skewing. Secondary transplantation documented continued production of LT-HSC with normal lineage differentiation. PGE-pre reduced development of DEARE cardiovascular pathologies and renal damage; prevented coronary artery rarefication, blunted progressive loss of coronary artery endothelia, reduced inflammation and coronary early senescence, and blunted radiation-induced increase in blood urea nitrogen (BUN). Ocular monocytes were significantly lower in PGE-pre mice, as was TBI-induced fur graying. Increased body weight and decreased frailty in male mice, and reduced incidence of thymic lymphoma were documented in PGE-pre mice. In assays measuring behavioral and cognitive functions, PGE-pre reduced anxiety in females, significantly blunted shock flinch response, and increased exploratory behavior in males. No effect of TBI was observed on memory in any group. PGE-post, despite significantly increasing 30-day survival in H-ARS and WBC and hematopoietic recovery, was not effective in reducing TBI-induced RBMD or any other DEARE. In summary, dmPGE2 administered as an H-ARS MCM before lethal TBI significantly increased 30-day survival and ameliorated RBMD and multi-organ and cognitive/behavioral DEARE to at least 12 months after TBI, whereas given after TBI, dmPGE2 enhances survival from H-ARS but has little impact on RBMD or other DEARE., (©2023 by Radiation Research Society. All rights of reproduction in any form reserved.)
- Published
- 2023
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3. Microglial knockdown does not affect acute withdrawal but delays analgesic tolerance from oxycodone in male and female C57BL/6J mice.
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El Jordi O, Fischer KD, Meyer TB, Atwood BK, Oblak AL, Pan RW, and McKinzie DL
- Abstract
Opioid Use Disorder (OUD) affects approximately 8%-12% of the population. In dependent individuals, abrupt cessation of opioid taking results in adverse withdrawal symptoms that reinforce drug taking behavior. Considerable unmet clinical need exists for new pharmacotherapies to treat opioid withdrawal as well as improve long-term abstinence. The neuroimmune system has received much scientific attention in recent years as a potential therapeutic target to combat various neurodegenerative and psychiatric disorders including addiction. However, the specific contribution of microglia has not been investigated in oxycodone dependence. Chronic daily treatment with the CSF1R inhibitor Pexidartinib (PLX3397) was administered to knockdown microglia expression and evaluate consequences on analgesia and on naloxone induced withdrawal from oxycodone. In vivo results indicated that an approximately 40% reduction in brain IBA1 staining was achieved in the PLX treatment group, which was associated with a delay in the development of analgesic tolerance to oxycodone and maintained antinociceptive efficacy. Acute withdrawal behavioral symptoms, brain astrocyte expression, and levels of many neuroinflammatory markers were not affected by PLX treatment. KC/GRO (also known as CXCL1) was significantly enhanced in the somatosensory cortex in oxycodone-treated mice receiving PLX. Microglial knock-down did not affect the expression of naloxoneinduced opioid withdrawal but affected antinociceptive responsivity. The consequences of increased KC/GRO expression within the somatosensory cortex due to microglial reduction during opioid dependence are unclear but may be important for neural pathways mediating opioid-induced analgesia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 El Jordi, Fischer, Meyer, Atwood, Oblak, Pan and McKinzie.)
- Published
- 2022
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4. Bassoon contributes to tau-seed propagation and neurotoxicity.
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Martinez P, Patel H, You Y, Jury N, Perkins A, Lee-Gosselin A, Taylor X, You Y, Viana Di Prisco G, Huang X, Dutta S, Wijeratne AB, Redding-Ochoa J, Shahid SS, Codocedo JF, Min S, Landreth GE, Mosley AL, Wu YC, McKinzie DL, Rochet JC, Zhang J, Atwood BK, Troncoso J, and Lasagna-Reeves CA
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- Animals, Mice, tau Proteins metabolism, Proteomics, Brain metabolism, Alzheimer Disease metabolism, Tauopathies metabolism
- Abstract
Tau aggregation is a defining histopathological feature of Alzheimer's disease and other tauopathies. However, the cellular mechanisms involved in tau propagation remain unclear. Here, we performed an unbiased quantitative proteomic study to identify proteins that specifically interact with this tau seed. We identified Bassoon (BSN), a presynaptic scaffolding protein, as an interactor of the tau seed isolated from a mouse model of tauopathy, and from Alzheimer's disease and progressive supranuclear palsy postmortem samples. We show that BSN exacerbates tau seeding and toxicity in both mouse and Drosophila models for tauopathy, and that BSN downregulation decreases tau spreading and overall disease pathology, rescuing synaptic and behavioral impairments and reducing brain atrophy. Our findings improve the understanding of how tau seeds can be stabilized by interactors such as BSN. Inhibiting tau-seed interactions is a potential new therapeutic approach for neurodegenerative tauopathies., (© 2022. The Author(s).)
- Published
- 2022
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5. Robust Pharmacodynamic Effect of LY3202626, a Central Nervous System Penetrant, Low Dose BACE1 Inhibitor, in Humans and Nonclinical Species.
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Willis BA, Lowe SL, Monk SA, Cocke PJ, Aluise CD, Boggs LN, Borders AR, Brier RA, Dean RA, Green SJ, James DE, Jhee SS, Lin Q, Lo AC, May PC, Watson BM, Winneroski LL, Yang Z, Zimmer JA, McKinzie DL, and Mergott DJ
- Abstract
Background: The development of beta-site amyloid-beta precursor protein cleaving enzyme (BACE) 1 inhibitors for the treatment of Alzheimer's disease requires optimization of inhibitor potency, selectivity, and brain penetration. Moreover, there is a need for low-dose compounds since liver toxicity was found with some BACE inhibitors., Objective: To determine whether the high in vitro potency and robust pharmacodynamic effect of the BACE inhibitor LY3202626 observed in nonclinical species translated to humans., Methods: The effect of LY3202626 versus vehicle on amyloid-β (Aβ) levels was evaluated in a series of in vitro assays, as well as in in vivo and multi-part clinical pharmacology studies. Aβ levels were measured using analytical biochemistry assays in brain, plasma, and cerebrospinal fluid (CSF) of mice, dogs and humans. Nonclinical data were analyzed using an ANOVA followed by Tukey's post hoc test and clinical data used summary statistics., Results: LY3202626 exhibited significant human BACE1 inhibition, with an IC
50 of 0.615±0.101 nM in a fluorescence resonance energy transfer assay and an EC50 of 0.275±0.176 nM for lowering Aβ1-40 and 0.228±0.244 nM for Aβ1-42 in PDAPP neuronal cultures. In dogs, CSF Aβ1hboxx concentrations were significantly reduced by ∼80% at 9 hours following a 1.5 mg/kg dose. In humans, CSF Aβ1-42 was reduced by 73.1±7.96 % following administration of 6 mg QD. LY3202626 was found to freely cross the blood-brain barrier in dogs and humans., Conclusion: LY3202626 is a potent BACE1 inhibitor with high blood-brain barrier permeability. The favorable safety and pharmacokinetic/pharmacodynamic profile of LY3202626 supports further clinical development., Competing Interests: BAW, SLL, SAM, PJC, CDA, LNB, ARB, RAB, RAD, SJG, DEJ, QL, ACL, PCM, BMW, LLW, ZY, JAZ, DLM, DJM are all employed by and minor stockholders in Eli Lilly and Company or were at the time these studies were conducted., (© 2022 – The authors. Published by IOS Press.)- Published
- 2022
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6. Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor.
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McKinzie DL, Winneroski LL, Green SJ, Hembre EJ, Erickson JA, Willis BA, Monk SA, Aluise CD, Baker TK, Lopez JE, Hendle J, Beck JP, Brier RA, Boggs LN, Borders AR, Cocke PJ, Garcia-Losada P, Lowe SL, Mathes BM, May PC, Porter WJ, Stout SL, Timm DE, Watson BM, Yang Z, and Mergott DJ
- Subjects
- Amyloid Precursor Protein Secretases metabolism, Animals, Aspartic Acid Endopeptidases metabolism, Blood-Brain Barrier physiology, Brain metabolism, Crystallography, X-Ray, Dogs, Drug Stability, Heterocyclic Compounds, 2-Ring chemical synthesis, Heterocyclic Compounds, 2-Ring pharmacokinetics, Humans, Madin Darby Canine Kidney Cells, Male, Mice, Microsomes, Liver metabolism, Molecular Structure, Protease Inhibitors chemical synthesis, Protease Inhibitors metabolism, Protease Inhibitors pharmacokinetics, Protein Binding, Pyrazines chemical synthesis, Pyrazines pharmacokinetics, Pyrroles chemical synthesis, Pyrroles pharmacokinetics, Rats, Structure-Activity Relationship, Amyloid Precursor Protein Secretases antagonists & inhibitors, Aspartic Acid Endopeptidases antagonists & inhibitors, Heterocyclic Compounds, 2-Ring pharmacology, Protease Inhibitors pharmacology, Pyrazines pharmacology, Pyrroles pharmacology
- Abstract
The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer's disease drug target owing to its critical role in the production of amyloid-beta. We have previously reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before development was terminated due to nonclinical retinal toxicity. LY2886721 advanced to Phase II, but development was halted due to abnormally elevated liver enzymes. Herein, we report the discovery and clinical development of LY3202626, a highly potent, CNS-penetrant, and low-dose BACE inhibitor, which successfully addressed these key development challenges.
- Published
- 2021
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7. Genetic Background and Sex: Impact on Generalizability of Research Findings in Pharmacology Studies.
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Sukoff Rizzo SJ, McTighe S, and McKinzie DL
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- Animals, Humans, Models, Animal, Mutation, Pharmacology, Clinical, Reproducibility of Results, Genetic Background, Genome
- Abstract
Animal models consisting of inbred laboratory rodent strains have been a powerful tool for decades, helping to unravel the underpinnings of biological problems and employed to evaluate potential therapeutic treatments in drug discovery. While inbred strains demonstrate relatively reliable and predictable responses, using a single inbred strain alone or as a background to a mutation is analogous to running a clinical trial in a single individual and their identical twins. Indeed, complex etiologies drive the most common human diseases, and a single inbred strain that is a surrogate of a single genome, or data generated from a single sex, is not representative of the genetically diverse patient populations. Further, pharmacological and toxicology data generated in otherwise healthy animals may not translate to disease states where physiology, metabolism, and general health are compromised. The purpose of this chapter is to provide guidance for improving generalizability of preclinical studies by providing insight into necessary considerations for introducing systematic variation within the study design, such as genetic diversity, the use of both sexes, and selection of appropriate age and disease model. The outcome of implementing these considerations should be that reproducibility and generalizability of significant results are significantly enhanced leading to improved clinical translation.
- Published
- 2020
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8. Chronic pain impairs cognitive flexibility and engages novel learning strategies in rats.
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Cowen SL, Phelps CE, Navratilova E, McKinzie DL, Okun A, Husain O, Gleason SD, Witkin JM, and Porreca F
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- Animals, Chronic Pain etiology, Decision Making physiology, Male, Peripheral Nerve Injuries complications, Peripheral Nerve Injuries psychology, Rats, Rats, Sprague-Dawley, Chronic Pain psychology, Cognition physiology, Executive Function physiology, Learning physiology
- Abstract
Cognitive flexibility, the ability to adapt behavior to changing outcomes, is critical to survival. The prefrontal cortex is a key site of cognitive control, and chronic pain is known to lead to significant morphological changes to this brain region. Nevertheless, the effects of chronic pain on cognitive flexibility and learning remain uncertain. We used an instrumental paradigm to assess adaptive learning in an experimental model of chronic pain induced by tight ligation of the spinal nerves L5/6 (spinal nerve ligation model). Naive, sham-operated, and spinal nerve ligation (SNL) rats were trained to perform fixed-ratio, variable-ratio, and contingency-shift behaviors for food reward. Although all groups learned an initial lever-reward contingency, learning was slower in SNL animals in a subsequent choice task that reversed reinforcement contingencies. Temporal analysis of lever-press responses across sessions indicated no apparent deficits in memory consolidation or retrieval. However, analysis of learning within sessions revealed that the lever presses of SNL animals occurred in bursts, followed by delays. Unexpectedly, the degree of bursting correlated positively with learning. Under a variable-ratio probabilistic task, SNL rats chose a less profitable behavioral strategy compared with naive and sham-operated animals. After extinction of behavior for learned preferences, SNL animals reverted to their initially preferred (ie, less profitable) behavioral choice. Our data suggest that in the face of uncertainty, chronic pain drives a preference for familiar associations, consistent with reduced cognitive flexibility. The observed burst-like responding may represent a novel learning strategy in animals with chronic pain.
- Published
- 2018
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9. Synthesis and Pharmacological Characterization of C4 β -Amide-Substituted 2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1 S,2 S,4 S,5 R,6 S)-2-Amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2794193), a Highly Potent and Selective mGlu 3 Receptor Agonist.
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Monn JA, Henry SS, Massey SM, Clawson DK, Chen Q, Diseroad BA, Bhardwaj RM, Atwell S, Lu F, Wang J, Russell M, Heinz BA, Wang XS, Carter JH, Getman BG, Adragni K, Broad LM, Sanger HE, Ursu D, Catlow JT, Swanson S, Johnson BG, Shaw DB, McKinzie DL, and Hao J
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- Animals, Bridged Bicyclo Compounds pharmacokinetics, Crystallography, X-Ray, Cyclic AMP pharmacology, Excitatory Amino Acid Agonists pharmacokinetics, Excitatory Amino Acid Antagonists pharmacology, Humans, Male, Models, Molecular, Molecular Docking Simulation, Molecular Structure, Motor Activity drug effects, Neurons drug effects, Neurons metabolism, Phencyclidine antagonists & inhibitors, Phencyclidine pharmacology, Protein Binding, Rats, Rats, Sprague-Dawley, Bridged Bicyclo Compounds chemical synthesis, Bridged Bicyclo Compounds pharmacology, Excitatory Amino Acid Agonists chemical synthesis, Excitatory Amino Acid Agonists pharmacology, Receptors, Metabotropic Glutamate agonists
- Abstract
Multiple therapeutic opportunities have been suggested for compounds capable of selective activation of metabotropic glutamate 3 (mGlu
3 ) receptors, but small molecule tools are lacking. As part of our ongoing efforts to identify potent, selective, and systemically bioavailable agonists for mGlu2 and mGlu3 receptor subtypes, a series of C4β -N-linked variants of (1 S,2 S,5 R,6 S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 1 (LY354740) were prepared and evaluated for both mGlu2 and mGlu3 receptor binding affinity and functional cellular responses. From this investigation we identified (1 S,2 S,4 S,5 R,6 S)-2-amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 8p (LY2794193), a molecule that demonstrates remarkable mGlu3 receptor selectivity. Crystallization of 8p with the amino terminal domain of hmGlu3 revealed critical binding interactions for this ligand with residues adjacent to the glutamate binding site, while pharmacokinetic assessment of 8p combined with its effect in an mGlu2 receptor-dependent behavioral model provides estimates for doses of this compound that would be expected to selectively engage and activate central mGlu3 receptors in vivo.- Published
- 2018
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10. Translational Pharmacology of the Metabotropic Glutamate 2 Receptor-Preferring Agonist LY2812223 in the Animal and Human Brain.
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Felder CC, Schober DA, Tu Y, Quets A, Xiao H, Watt M, Siuda E, Nisenbaum E, Xiang C, Heinz B, Prieto L, McKinzie DL, and Monn JA
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- Animals, Brain metabolism, Bridged Bicyclo Compounds metabolism, Dose-Response Relationship, Drug, Excitatory Amino Acid Agonists metabolism, Humans, Mice, Mice, Knockout, Protein Binding drug effects, Protein Binding physiology, Rats, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate metabolism, Translational Research, Biomedical, Triazoles metabolism, Brain drug effects, Bridged Bicyclo Compounds pharmacology, Drug Partial Agonism, Excitatory Amino Acid Agonists pharmacology, Receptors, Metabotropic Glutamate agonists, Triazoles pharmacology
- Abstract
LY2812223 [(1 R ,2 S ,4 R ,5 R ,6 R )-2-amino-4-(1 H -1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid] was identified via structure-activity studies arising from the potent metabotropic glutamate mGlu2/3 receptor agonist LY354740 [(+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid] as an mGlu2-preferring agonist. This pharmacology was determined using stably transfected cells containing either the human mGlu2 or mGlu3 receptor. We extended the pharmacological evaluation of LY2812223 to native brain tissues derived from relevant species used for preclinical drug development as well as human postmortem brain tissue. This analysis was conducted to ensure pharmacological translation from animals to human subjects in subsequent clinical studies. A guanosine 5'- O -(3-[
35 S]thio)triphosphate (GTP γ S) functional binding assay, a method for measuring Gi -coupled signaling that is inherent to the group 2 mGlu receptors, was used to evaluate LY2812223 pharmacology of native mGlu receptors in mouse, rat, nonhuman primate, and human cortical brain tissue samples. In native tissue membranes, LY2812223 unexpectedly acted as a partial agonist across all species tested. Activity of LY2812223 was lost in cortical membranes collected from mGlu2 knockout mice, but not those from mGlu3 knockout mice, providing additional support for mGlu2-preferring activity. Other signal transduction assays were used for comparison with the GTP binding assay (cAMP, calcium mobilization, and dynamic mass redistribution). In ectopic cell line-based assays, LY2812223 displayed near maximal agonist responses at the mGlu2 receptor across all assay formats, while it showed no functional agonist activity at the mGlu3 receptor except in the cAMP assay. In native brain slices or membranes that express both mGlu2 and mGlu3 receptors, LY2812223 displayed unexpected partial agonist activity, which may suggest a functional interplay between these receptor subtypes in the brain., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)- Published
- 2017
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11. Hedonic and motivational responses to food reward are unchanged in rats with neuropathic pain.
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Okun A, McKinzie DL, Witkin JM, Remeniuk B, Husein O, Gleason SD, Oyarzo J, Navratilova E, McElroy B, Cowen S, Kennedy JD, and Porreca F
- Subjects
- Animals, Conditioning, Operant drug effects, Conditioning, Operant physiology, Disease Models, Animal, Extinction, Psychological physiology, Freund's Adjuvant toxicity, Male, Neuralgia etiology, Pain Measurement, Rats, Rats, Sprague-Dawley, Spinal Nerves injuries, Sucrose administration & dosage, Taste drug effects, Time Factors, Food, Motivation physiology, Neuralgia physiopathology, Neuralgia psychology, Reward
- Abstract
Rewards influence responses to acute painful stimuli, but the relationship of chronic pain to hedonic or motivational aspects of reward is not well understood. We independently evaluated hedonic qualities of sweet or bitter tastants and motivation to seek food reward in rats with experimental neuropathic pain induced by L5/6 spinal nerve ligation. Hedonic response was measured by implantation of intraoral catheters to allow passive delivery of liquid solutions, and "liking/disliking" responses were scored according to a facial reactivity scale. Spinal nerve ligation rats did not differ from controls in either "liking" or "disliking" reactions to intraoral sucrose or quinine, respectively, at postsurgery day 21, suggesting no differences in perceived hedonic value of sweet or bitter tastants. To assess possible motivational deficits during acute and chronic pain, we used fixed- and progressive-ratio response paradigms of sucrose pellet presentation in rats with transient inflammatory or chronic neuropathic pain. Assessment of response acquisition and break points under the progressive ratio schedule revealed no differences between sham and spinal nerve ligation rats for up to 120 days after injury. However, rats with inflammation showed decrements in lever pressing and break points on days 1 and 2 after complete Freund adjuvant injection that normalized by day 4, consistent with transient ongoing pain. Thus, although acute ongoing inflammatory pain may transiently reduce reward motivation, we did not detect influences of chronic neuropathic pain on hedonic or motivational responses to food rewards. Adaptations that allow normal reward responding to food regardless of chronic pain may be of evolutionary benefit to promote survival., Competing Interests: We have no conflicts of interest to declare.
- Published
- 2016
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12. Preclinical findings predicting efficacy and side-effect profile of LY2940094, an antagonist of nociceptin receptors.
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Witkin JM, Rorick-Kehn LM, Benvenga MJ, Adams BL, Gleason SD, Knitowski KM, Li X, Chaney S, Falcone JF, Smith JW, Foss J, Lloyd K, Catlow JT, McKinzie DL, Svensson KA, Barth VN, Toledo MA, Diaz N, Lafuente C, Jiménez A, Benito A, Pedregal C, Martínez-Grau MA, Post A, Ansonoff MA, Pintar JE, and Statnick MA
- Abstract
Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide whose receptor is designated ORL1 or nociceptin receptor (NOP). We utilized a potent, selective, and orally bioavailable antagonist with documented engagement with NOP receptors in vivo to assess antidepressant- and anxiolytic-related pharmacological effects of NOP receptor blockade along with measures of cognitive and motor impingement. LY2940094 ([2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol) displayed antidepressant-like behavioral effects in the forced-swim test in mice, an effect absent in NOP
-/- mice. LY2940094 also augmented the behavioral effect of fluoxetine without changing target occupancies (NOP and serotonin reuptake transporter [SERT]). LY2940094 did not have effects under a differential-reinforcement of low rate schedule. Although anxiolytic-like effects were not observed in some animal models (conditioned suppression, 4-plate test, novelty-suppressed feeding), LY2940094 had effects like that of anxiolytic drugs in three assays: fear-conditioned freezing in mice, stress-induced increases in cerebellar cGMP in mice, and stress-induced hyperthermia in rats. These are the first reports of anxiolytic-like activity with a systemically viable NOP receptor antagonist. LY2940094 did not disrupt performance in either a 5-choice serial reaction time or delayed matching-to-position assay. LY2940094 was also not an activator or suppressor of locomotion in rodents nor did it induce failures of rotarod performance. These data suggest that LY2940094 has unique antidepressant- and anxiolytic-related pharmacological effects in rodents. Clinical proof of concept data on this molecule in depressed patients have been reported elsewhere.- Published
- 2016
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13. Exploratory analysis for a targeted patient population responsive to the metabotropic glutamate 2/3 receptor agonist pomaglumetad methionil in schizophrenia.
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Kinon BJ, Millen BA, Zhang L, and McKinzie DL
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- Adolescent, Adult, Aged, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Middle Aged, Psychiatric Status Rating Scales, Randomized Controlled Trials as Topic, Treatment Outcome, Young Adult, Antipsychotic Agents therapeutic use, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Cyclic S-Oxides therapeutic use, Receptors, Metabotropic Glutamate agonists, Schizophrenia drug therapy
- Abstract
Background: Accumulating evidence indicates that glutamatergic tone in schizophrenia may vary as a function of illness duration or medication history. We conducted an exploratory analysis of the existing clinical trial database of pomaglumetad methionil (pomaglumetad) to demonstrate treatment response in targeted patient populations., Methods: Results of the H8Y-MC-HBBM (HBBM) study and an integrated analysis based on five placebo-controlled trials were summarized. Patients with schizophrenia were randomly assigned to receive either pomaglumetad, 40 or 80 mg twice daily (BID), placebo, or risperidone, 2 mg BID, for up to 6 weeks. Patient subgroups were analyzed to determine the efficacy of pomaglumetad treatment in patients early-in-disease (≤3 years) and late-in-disease (≥10 years) (HBBM, 40 mg, n = 206, 80 mg, n = 198; integrated analysis, 40 mg, n = 382, 80 mg, n = 381) and in patients previously treated with central nervous system drugs with prominent serotonin 2A receptor antagonist activity (S2 group) or with predominant dopamine D2 receptor antagonist activity (D2 group; HBBM, 40 mg, n = 275, 80 mg, n = 269; integrated analysis, 40 mg, n = 590, 80 mg, n = 506)., Results: In the HBBM study and integrated analysis, only patients early-in-disease or previously treated with D2 drugs exhibited significantly greater improvement relative to those receiving placebo, when treated with pomaglumetad, 40 mg (but not 80 mg) BID. Treatment response to risperidone did not appear to depend upon these patient subgroups., Conclusions: Demonstration of antipsychotic efficacy of a potential glutamate-based pharmacotherapy for schizophrenia may require the identification of appropriate patient subgroups whose treatment responsiveness may be fundamentally related to dysregulation of central nervous system glutamatergic tone., (Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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14. Design and synthesis of N-[6-(Substituted Aminoethylideneamino)-2-Hydroxyindan-1-yl]arylamides as selective and potent muscarinic M₁ agonists.
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Liu B, Croy CH, Hitchcock SA, Allen JR, Rao Z, Evans D, Bures MG, McKinzie DL, Watt ML, Stuart Gregory G, Hansen MM, Hoogestraat PJ, Jamison JA, Okha-Mokube FM, Stratford RE, Turner W, Bymaster F, and Felder CC
- Subjects
- Amides chemical synthesis, Animals, Dose-Response Relationship, Drug, Humans, Molecular Structure, Rats, Structure-Activity Relationship, Amides chemistry, Amides pharmacology, Drug Design, Receptor, Muscarinic M1 agonists
- Abstract
The observation that cholinergic deafferentation of circuits projecting from forebrain basal nuclei to frontal and hippocampal circuits occurs in Alzheimer's disease has led to drug-targeting of muscarinic M1 receptors to alleviate cognitive symptoms. The high homology within the acetylcholine binding domain of this family however has made receptor-selective ligand development challenging. This work presents the synthesis scheme, pharmacokinetic and structure-activity-relationship study findings for M1-selective ligand, LY593093. Pharmacologically the compound acts as an orthosteric ligand. The homology modeling work presented however will illustrate that compound binding spans from the acetylcholine pocket to the extracellular loops of the receptor, a common allosteric vestibule for the muscarinic protein family. Altogether LY593093 represents a growing class of multi-topic ligands which interact with the receptors in both the ortho- and allosteric binding sites, but which exert their activation mechanism as an orthosteric ligand., (Copyright © 2015. Published by Elsevier Ltd.)
- Published
- 2015
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15. Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu2 Receptor Agonist.
- Author
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Monn JA, Prieto L, Taboada L, Hao J, Reinhard MR, Henry SS, Beadle CD, Walton L, Man T, Rudyk H, Clark B, Tupper D, Baker SR, Lamas C, Montero C, Marcos A, Blanco J, Bures M, Clawson DK, Atwell S, Lu F, Wang J, Russell M, Heinz BA, Wang X, Carter JH, Getman BG, Catlow JT, Swanson S, Johnson BG, Shaw DB, and McKinzie DL
- Subjects
- Allosteric Regulation, Animals, Binding, Competitive, Bridged Bicyclo Compounds pharmacokinetics, Bridged Bicyclo Compounds pharmacology, Calcium metabolism, Cyclic AMP metabolism, Dogs, Drug Partial Agonism, Humans, Male, Mice, Models, Molecular, Motor Activity drug effects, Mutagenesis, Site-Directed, Protein Structure, Tertiary, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate antagonists & inhibitors, Receptors, Metabotropic Glutamate genetics, Receptors, Metabotropic Glutamate metabolism, Stereoisomerism, Triazoles pharmacokinetics, Triazoles pharmacology, Bridged Bicyclo Compounds chemistry, Receptors, Metabotropic Glutamate agonists, Triazoles chemistry
- Abstract
Identification of orthosteric mGlu(2/3) receptor agonists capable of discriminating between individual mGlu2 and mGlu3 subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other recombinant human mGlu2/3 subtypes, a number of high potency and efficacy mGlu2 receptor agonists exhibiting low potency mGlu3 partial agonist/antagonist activity were identified. From this, (1R,2S,4R,5R,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 14a (LY2812223) was further characterized. Cocrystallization of 14a with the amino terminal domains of hmGlu2 and hmGlu3 combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu2 receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu2 receptors in vivo.
- Published
- 2015
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16. Synthesis and pharmacological characterization of C4-disubstituted analogs of 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate: identification of a potent, selective metabotropic glutamate receptor agonist and determination of agonist-bound human mGlu2 and mGlu3 amino terminal domain structures.
- Author
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Monn JA, Prieto L, Taboada L, Pedregal C, Hao J, Reinhard MR, Henry SS, Goldsmith PJ, Beadle CD, Walton L, Man T, Rudyk H, Clark B, Tupper D, Baker SR, Lamas C, Montero C, Marcos A, Blanco J, Bures M, Clawson DK, Atwell S, Lu F, Wang J, Russell M, Heinz BA, Wang X, Carter JH, Xiang C, Catlow JT, Swanson S, Sanger H, Broad LM, Johnson MP, Knopp KL, Simmons RM, Johnson BG, Shaw DB, and McKinzie DL
- Subjects
- Animals, Bridged Bicyclo Compounds chemistry, Bridged Bicyclo Compounds metabolism, Crystallography, X-Ray, Humans, Male, Models, Molecular, Protein Structure, Tertiary, Rats, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate chemistry, Receptors, Metabotropic Glutamate genetics, Spiro Compounds chemistry, Spiro Compounds metabolism, Bridged Bicyclo Compounds pharmacology, Receptors, Metabotropic Glutamate agonists, Spiro Compounds pharmacology
- Abstract
As part of our ongoing research to identify novel agents acting at metabotropic glutamate 2 (mGlu2) and 3 (mGlu3) receptors, we have previously reported the identification of the C4α-methyl analog of mGlu2/3 receptor agonist 1 (LY354740). This molecule, 1S,2S,4R,5R,6S-2-amino-4-methylbicyclo[3.1.0]hexane-2,6-dicarboxylate 2 (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3 antagonist pharmacological profile, whereas the C4β-methyl diastereomer (3) possessed dual mGlu2/3 receptor agonist activity. We have now further explored this structure-activity relationship through the preparation of cyclic and acyclic C4-disubstituted analogs of 1, leading to the identification of C4-spirocyclopropane 5 (LY2934747), a novel, potent, and systemically bioavailable mGlu2/3 receptor agonist which exhibits both antipsychotic and analgesic properties in vivo. In addition, through the combined use of protein-ligand X-ray crystallography employing recombinant human mGlu2/3 receptor amino terminal domains, molecular modeling, and site-directed mutagenesis, a molecular basis for the observed pharmacological profile of compound 2 is proposed.
- Published
- 2015
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17. Determining pharmacological selectivity of the kappa opioid receptor antagonist LY2456302 using pupillometry as a translational biomarker in rat and human.
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Rorick-Kehn LM, Witcher JW, Lowe SL, Gonzales CR, Weller MA, Bell RL, Hart JC, Need AB, McKinzie JH, Statnick MA, Suico JG, McKinzie DL, Tauscher-Wisniewski S, Mitch CH, Stoltz RR, and Wong CJ
- Subjects
- Adolescent, Adult, Animals, Benzamides blood, Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Fentanyl pharmacology, Humans, Male, Middle Aged, Miosis chemically induced, Miosis drug therapy, Morphine pharmacology, Mydriasis chemically induced, Mydriasis drug therapy, Naltrexone pharmacology, Narcotic Antagonists blood, Narcotics pharmacology, Pupil physiology, Pyrrolidines blood, Rats, Sprague-Dawley, Receptors, Opioid, kappa agonists, Receptors, Opioid, kappa metabolism, Young Adult, Benzamides pharmacology, Narcotic Antagonists pharmacology, Pupil drug effects, Pyrrolidines pharmacology, Receptors, Opioid, kappa antagonists & inhibitors
- Abstract
Background: Selective kappa opioid receptor antagonism is a promising experimental strategy for the treatment of depression. The kappa opioid receptor antagonist, LY2456302, exhibits ~30-fold higher affinity for kappa opioid receptors over mu opioid receptors, which is the next closest identified pharmacology., Methods: Here, we determined kappa opioid receptor pharmacological selectivity of LY2456302 by assessing mu opioid receptor antagonism using translational pupillometry in rats and humans., Results: In rats, morphine-induced mydriasis was completely blocked by the nonselective opioid receptor antagonist naloxone (3mg/kg, which produced 90% mu opioid receptor occupancy), while 100 and 300 mg/kg LY2456302 (which produced 56% and 87% mu opioid receptor occupancy, respectively) only partially blocked morphine-induced mydriasis. In humans, fentanyl-induced miosis was completely blocked by 50mg naltrexone, and LY2456302 dose-dependently blocked miosis at 25 and 60 mg (minimal-to-no blockade at 4-10mg)., Conclusions: We demonstrate, for the first time, the use of translational pupillometry in the context of receptor occupancy to identify a clinical dose of LY2456302 achieving maximal kappa opioid receptor occupancy without evidence of significant mu receptor antagonism., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)
- Published
- 2014
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18. LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders.
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Rorick-Kehn LM, Witkin JM, Statnick MA, Eberle EL, McKinzie JH, Kahl SD, Forster BM, Wong CJ, Li X, Crile RS, Shaw DB, Sahr AE, Adams BL, Quimby SJ, Diaz N, Jimenez A, Pedregal C, Mitch CH, Knopp KL, Anderson WH, Cramer JW, and McKinzie DL
- Subjects
- Analgesia, Animals, Antidepressive Agents pharmacokinetics, Antidepressive Agents pharmacology, Antidepressive Agents therapeutic use, Benzamides pharmacokinetics, Benzamides therapeutic use, Disease Models, Animal, Ethanol administration & dosage, Male, Mice, Narcotic Antagonists pharmacokinetics, Narcotic Antagonists therapeutic use, Pyrrolidines pharmacokinetics, Pyrrolidines therapeutic use, Rats, Self Administration, Benzamides pharmacology, Depression drug therapy, Narcotic Antagonists pharmacology, Pyrrolidines pharmacology, Receptors, Opioid, kappa antagonists & inhibitors, Reflex, Startle drug effects, Sensory Gating drug effects
- Abstract
Kappa opioid receptors and their endogenous neuropeptide ligand, dynorphin A, are densely localized in limbic and cortical areas comprising the brain reward system, and appear to play a key role in modulating stress and mood. Growing literature indicates that kappa receptor antagonists may be beneficial in the treatment of mood and addictive disorders. However, existing literature on kappa receptor antagonists has used extensively JDTic and nor-BNI which exhibit long-lasting pharmacokinetic properties that complicate experimental design and interpretation of results. Herein, we report for the first time the in vitro and in vivo pharmacological profile of a novel, potent kappa opioid receptor antagonist with excellent selectivity over other receptors and markedly improved drug-like properties over existing research tools. LY2456302 exhibits canonical pharmacokinetic properties that are favorable for clinical development, with rapid absorption (t(max): 1-2 h) and good oral bioavailability (F = 25%). Oral LY2456302 administration selectively and potently occupied central kappa opioid receptors in vivo (ED₅₀ = 0.33 mg/kg), without evidence of mu or delta receptor occupancy at doses up to 30 mg/kg. LY2456302 potently blocked kappa-agonist-mediated analgesia and disruption of prepulse inhibition, without affecting mu-agonist-mediated effects at doses >30-fold higher. Importantly, LY2456302 did not block kappa-agonist-induced analgesia one week after administration, indicating lack of long-lasting pharmacodynamic effects. In contrast to the nonselective opioid antagonist naltrexone, LY2456302 produced antidepressant-like effects in the mouse forced swim test and enhanced the effects of imipramine and citalopram. LY2456302 reduced ethanol self-administration in alcohol-preferring (P) rats and, unlike naltrexone, did not exhibit significant tolerance upon 4 days of repeated dosing. LY2456302 is a centrally-penetrant, potent, kappa-selective antagonist with pharmacokinetic properties favorable for clinical development and activity in animal models predictive of efficacy in mood and addictive disorders., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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19. The muscarinic acetylcholine receptor agonist BuTAC mediates antipsychotic-like effects via the M4 subtype.
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Watt ML, Rorick-Kehn L, Shaw DB, Knitowski KM, Quets AT, Chesterfield AK, McKinzie DL, and Felder CC
- Subjects
- Analysis of Variance, Animals, Avoidance Learning physiology, CHO Cells, Conditioning, Operant physiology, Cricetulus, Dose-Response Relationship, Drug, Guanosine 5'-O-(3-Thiotriphosphate) pharmacokinetics, Haloperidol pharmacology, Mice, Mice, Inbred C57BL, Mice, Knockout, Protein Binding drug effects, Receptor, Muscarinic M2 genetics, Receptor, Muscarinic M2 metabolism, Receptor, Muscarinic M4 deficiency, Antipsychotic Agents pharmacology, Avoidance Learning drug effects, Conditioning, Operant drug effects, Receptor, Muscarinic M4 metabolism, Tropanes pharmacology
- Abstract
The generation of muscarinic acetylcholine receptor (mAChR) subtype-selective compounds has been challenging, requiring use of nonpharmacological approaches, such as genetically engineered animals, to deepen our understanding of the potential that members of the muscarinic receptor subtype family hold as therapeutic drug targets. The muscarinic receptor agonist 'BuTAC' was previously shown to exhibit efficacy in animal models of psychosis, although the particular receptor subtype(s) responsible for such activity was unclear. Here, we evaluate the in vitro functional agonist and antagonist activity of BuTAC using an assay that provides a direct measure of G protein activation. In addition, we employ the conditioned avoidance response paradigm, an in vivo model predictive of antipsychotic activity, and mouse genetic deletion models to investigate which presynaptic mAChR subtype mediates the antipsychotic-like effects of BuTAC. Our results show that, in vitro, BuTAC acts as a full agonist at the M2AChR and a partial agonist at the M1 and M4 receptors, with full antagonist activity at M3- and M5AChRs. In the mouse conditioned avoidance response (CAR) assay, BuTAC exhibits an atypical antipsychotic-like profile by selectively decreasing avoidance responses at doses that do not induce escape failures. CAR results using M2(-/-), M4(-/-), and M2/M4 (M2/M4(-/-)) mice found that the effects of BuTAC were near completely lost in M2/M4(-/-) double-knockout mice and potency of BuTAC was right-shifted in M4(-/-) as compared with wild-type and M2(-/-) mice. The M2/M4(-/-) mice showed no altered sensitivity to the antipsychotic effects of either haloperidol or clozapine, suggesting that these compounds mediate their actions in CAR via a non-mAChR-mediated mechanism. These data support a role for the M4AChR subtype in mediating the antipsychotic-like activity of BuTAC and implicate M4AChR agonism as a potential novel therapeutic mechanism for ameliorating symptoms associated with schizophrenia.
- Published
- 2013
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20. Synthesis and pharmacological characterization of 4-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates: identification of new potent and selective metabotropic glutamate 2/3 receptor agonists.
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Monn JA, Valli MJ, Massey SM, Hao J, Reinhard MR, Bures MG, Heinz BA, Wang X, Carter JH, Getman BG, Stephenson GA, Herin M, Catlow JT, Swanson S, Johnson BG, McKinzie DL, and Henry SS
- Subjects
- Administration, Oral, Amino Acids, Dicarboxylic pharmacokinetics, Amino Acids, Dicarboxylic pharmacology, Animals, Antipsychotic Agents pharmacokinetics, Antipsychotic Agents pharmacology, Bridged Bicyclo Compounds pharmacokinetics, Bridged Bicyclo Compounds pharmacology, Cyclohexanes pharmacokinetics, Cyclohexanes pharmacology, Humans, Male, Models, Molecular, Motor Activity drug effects, Psychotic Disorders drug therapy, Psychotic Disorders psychology, Rats, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate metabolism, Stereoisomerism, Structure-Activity Relationship, Amino Acids, Dicarboxylic chemical synthesis, Antipsychotic Agents chemical synthesis, Bridged Bicyclo Compounds chemical synthesis, Cyclohexanes chemical synthesis, Receptors, Metabotropic Glutamate agonists
- Abstract
As part of our ongoing interest in identifying novel agonists acting at metabotropic glutamate (mGlu) 2/3 receptors, we have explored the effect of structural modifications of 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate (LY354740), a potent and pharmacologically balanced mGlu2/3 receptor agonist. Incorporation of relatively small substituents (e.g., F, O) at the C4 position of this molecule resulted in additional highly potent mGlu2/3 agonists that demonstrate excellent selectivity over the other mGlu receptor subtypes, while addition of larger C4-substituents (e.g., SPh) led to a loss of agonist potency and/or the appearance of weak mGlu2/3 receptor antagonist activity. Further characterization of the α-fluoro-substituted analogue (LY459477) in vivo revealed that this molecule possesses good oral bioavailability in rats and effectively suppresses phencyclidine-evoked locomotor activity at doses that do not impair neuromuscular coordination. This molecule therefore represents a valuable new addition to the arsenal of pharmacological tools competent to investigate mGlu2/3 receptor function both in vitro and in vivo.
- Published
- 2013
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21. Discovery of (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide, a potent and orally efficacious mGlu5 receptor negative allosteric modulator.
- Author
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Hao J, Dehlinger V, Fivush AM, Rudyk HC, Britton TC, Hollinshead SP, Vokits BP, Clark BP, Henry SS, Massey SM, Peng L, Dressman BA, Heinz BA, Roberts EF, Bracey-Walker MR, Swanson S, Catlow JT, Love PL, Tepool AD, Peters SC, Simmons RM, Iyengar S, McKinzie DL, and Monn JA
- Subjects
- Allosteric Regulation drug effects, Amides pharmacokinetics, Animals, Behavior, Animal drug effects, Cyclopropanes pharmacokinetics, Glutamic Acid chemistry, Glutamic Acid metabolism, Indazoles chemistry, Indazoles pharmacokinetics, Indazoles pharmacology, Male, Rats, Rats, Sprague-Dawley, Receptor, Metabotropic Glutamate 5 chemistry, Thiazoles chemistry, Thiazoles pharmacokinetics, Thiazoles pharmacology, Amides chemistry, Amides pharmacology, Cyclopropanes chemistry, Cyclopropanes pharmacology, Receptor, Metabotropic Glutamate 5 metabolism
- Abstract
A novel series of selective negative allosteric modulators (NAMs) for metabotropic glutamate receptor 5 (mGlu5) was discovered from an isothiazole scaffold. One compound of this series, (1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide (24), demonstrated satisfactory pharmacokinetic properties and, following oral dosing in rats, produced dose-dependent and long-lasting mGlu5 receptor occupancy. Consistent with the hypothesis that blockade of mGlu5 receptors will produce analgesic effects in mammals, compound 24 produced a dose-dependent reduction in paw licking responses in the formalin model of persistent pain., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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22. The long-lasting effects of JDTic, a kappa opioid receptor antagonist, on the expression of ethanol-seeking behavior and the relapse drinking of female alcohol-preferring (P) rats.
- Author
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Deehan GA Jr, McKinzie DL, Carroll FI, McBride WJ, and Rodd ZA
- Subjects
- Alcohol Drinking physiopathology, Alcoholism drug therapy, Alcoholism physiopathology, Alcoholism psychology, Animals, Behavior, Addictive drug therapy, Behavior, Addictive physiopathology, Behavior, Addictive psychology, Conditioning, Operant drug effects, Drug-Seeking Behavior physiology, Ethanol administration & dosage, Female, Rats, Receptors, Opioid, kappa physiology, Recurrence, Reinforcement, Psychology, Self Administration, Alcohol Drinking drug therapy, Alcohol Drinking psychology, Drug-Seeking Behavior drug effects, Piperidines pharmacology, Receptors, Opioid, kappa antagonists & inhibitors, Tetrahydroisoquinolines pharmacology
- Abstract
The current study assessed the effects of the selective kappa opioid antagonist JDTic on alcohol (EtOH)-seeking behavior, EtOH relapse, and maintenance responding for EtOH. Adult alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) on a fixed-ratio 5 (FR-5) and water on a FR-1 schedule of reinforcement during 1-hr sessions. After 10 weeks, rats underwent extinction training for seven sessions. Rats were then maintained in their home cages for 3 weeks without EtOH access. All rats received an injection (s.c.) of 0, 1, 3, or 10 mg/kg JDTic (n=11-14/group) after the first week of the home cage period. Rats were then tested using the Pavlovian Spontaneous Recovery paradigm (PSR; an animal model of alcohol-seeking) for four sessions during which, responses on the EtOH and water levers were recorded but did not produce their respective reinforcer. Following PSR testing rats were returned to their home cages without access to EtOH for one week prior to the start of EtOH relapse testing. To examine EtOH relapse responding, rats were returned to the operant chambers and the EtOH (FR5) and water (FR1) levers were active. Finally, rats were then tested over 17 operant sessions to assess the effects of JDTic on maintenance responding for EtOH. Rats received 0, 1, 3, or 10 mg/kg JDTic (counterbalanced from the initial experiment) 30 minutes prior to the initial maintenance session. JDTic administered 14 and 25 days prior to testing dose-dependently reduced the expression of an EtOH PSR and relapse responding. In contrast, JDTic did not alter EtOH responding under maintenance conditions. Overall, the results of this study indicate that different mechanisms mediate EtOH self-administration under relapse and maintenance conditions and kappa opioid receptors are involved in mediating EtOH-seeking behavior and relapse responding but not on-going EtOH self-administration., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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23. Group II metabotropic glutamate receptor agonists and positive allosteric modulators as novel treatments for schizophrenia.
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Fell MJ, McKinzie DL, Monn JA, and Svensson KA
- Subjects
- Allosteric Regulation drug effects, Animals, Excitatory Amino Acid Agonists pharmacology, Humans, Signal Transduction drug effects, Excitatory Amino Acid Agonists therapeutic use, Receptors, Metabotropic Glutamate agonists, Receptors, Metabotropic Glutamate physiology, Schizophrenia drug therapy, Schizophrenia metabolism
- Abstract
Schizophrenia is a devastating chronic psychotic disorder characterized by positive, negative, and cognitive symptoms. Although the positive symptoms are relatively well controlled by current monoamine-based treatments for schizophrenia, these agents provide only modest efficacy against the negative and cognitive symptoms of the disease. Furthermore serious adverse events have been reported during treatment with antipsychotic drugs. Therefore, novel treatment strategies are needed that provide improved efficacy across the multiple symptom domains of schizophrenia and have improved tolerability/safety profiles. Glutamate is the primary excitatory neurotransmitter in the mammalian central nervous system (CNS) and plays an important role in physiological and pathological processes of the CNS. Group II metabotropic glutamate receptors (mGlu receptors), in particular, have been shown to modulate glutamatergic activity in brain synapses thought to be involved in the pathophysiology of schizophrenia. In recent years a number of selective mGlu2/3 receptor agonists and mGlu2 positive allosteric modulators have been disclosed with demonstrated efficacy in multiple animal models for schizophrenia. Consistent with predictions from pre-clinical animal studies, LY2140023 monohydrate, an mGlu2/3 receptor agonist prodrug, recently demonstrated evidence for antipsychotic activity in phase II proof of concept study. Although additional efficacy and safety studies are needed to understand the therapeutic potential of LY2140023, emerging preclinical and clinical data suggest that activation of group II mGlu receptors is a mechanistically novel and promising approach for the treatment of schizophrenia., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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24. Effects of naltrexone and LY255582 on ethanol maintenance, seeking, and relapse responding by alcohol-preferring (P) rats.
- Author
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Dhaher R, Toalston JE, Hauser SR, Bell RL, McKinzie DL, McBride WJ, and Rodd ZA
- Subjects
- Animals, Conditioning, Operant, Extinction, Psychological, Female, Rats, Secondary Prevention, Alcohol Drinking prevention & control, Central Nervous System Depressants administration & dosage, Cyclohexanes pharmacology, Drug-Seeking Behavior drug effects, Ethanol administration & dosage, Naltrexone pharmacology, Narcotic Antagonists pharmacology, Piperidines pharmacology
- Abstract
Research indicates opioid antagonists can reduce alcohol drinking in rodents. However, tests examining the effects of opioid antagonists on ethanol seeking and relapse behavior have been limited. The present study examined the effects of two opioid antagonists on ethanol maintenance, seeking, and relapse responding by alcohol-preferring (P) rats. Adult P rats were self-trained in two-lever operant chambers to self-administer 15% (vol/vol) ethanol on a fixed-ratio 5 (FR5) versus water on a FR1 concurrent schedule of reinforcement in daily 1-h sessions. After 10 weeks, rats underwent extinction training, followed by 2 weeks in their home cages. Rats were then returned to the operant chambers without ethanol or water to measure responses on the ethanol and water levers for four sessions. After a subsequent 2 weeks in the home cage, without access to ethanol, rats were returned to the operant chambers with ethanol and water available. Effects of antagonists on maintenance responding were tested after several weeks of daily 1-h sessions. Naltrexone (NAL; 1-10mg/kg, subcutaneously [s.c.]; n=8/dose), LY255582 (LY; 0.03-1mg/kg, s.c.; n=8/dose), or vehicle were injected 30min before the first session (in the absence of ethanol), following 2 weeks in their home cages, and for four consecutive sessions of ethanol self-administration under maintenance and relapse conditions. Both NAL and LY reduced responses on the ethanol lever without any fluids present, and ethanol self-administration under relapse and on-going drinking conditions, with LY being more potent than NAL. Both NAL and LY were less effective in reducing responding in the absence of ethanol than in reducing ethanol self-administration. Overall, the results indicate that the opioid system is involved in mediating ethanol seeking, and ethanol self-administration under relapse and on-going alcohol drinking, but that different neurocircuits may underlie these behaviors., (Published by Elsevier Inc.)
- Published
- 2012
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25. Reduction of dendritic spines and elevation of GABAergic signaling in the brains of mice treated with an estrogen receptor β ligand.
- Author
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Tan XJ, Dai YB, Wu WF, Kim HJ, Barros RP, Richardson TI, Yaden BC, Warner M, McKinzie DL, Krishnan V, and Gustafsson JÅ
- Subjects
- Animals, Brain metabolism, Dendritic Spines metabolism, Estrogen Receptor beta metabolism, Ligands, Mice, Receptors, N-Methyl-D-Aspartate metabolism, Benzopyrans pharmacology, Brain drug effects, Dendritic Spines drug effects, Estrogen Receptor beta drug effects, Signal Transduction, gamma-Aminobutyric Acid metabolism
- Abstract
An estrogen receptor (ER) β ligand (LY3201) with a preference for ERβ over ERα was administered in s.c. pellets releasing 0.04 mg/d. The brains of these mice were examined 3 d after treatment had begun. Although estradiol-17β is known to increase spine density and glutaminergic signaling, as measured by Golgi staining, a clear reduction in spines was evident on the dendritic branches in LY3201-treated mice but no morphological alteration and no difference in the number of dendritic spines on dendritic stems were observed. In the LY3201-treatment group, there was higher expression of glutamic acid decarboxylase (GAD) in layer V of cortex and in the CA1 of hippocampus, more GAD(+) terminals surrounding the pyramidal neurons and less glutamate receptor (NMDAR) on the neurons in layer V. There were no alterations in expression of Iba1 or in Olig2 or CNPase. However, GFAP(+) astrocytes were increased in the LY3201-treatment group. There were also more projections characteristic of activated astrocytes and increased expression of glutamine synthetase (GS). No expression of ERβ was detectable in the nuclei of astrocytes. Clearly, LY3201 caused a shift in the balance between excitatory and inhibitory neurotransmission in favor of inhibition. This shift was due in part to increased synthesis of GABA and increased removal of glutamate from the synaptic cleft by astrocytes. The data reveal that treatment with a selective ERβ agonist results in changes opposite to those reported in estradiol-17β-treated mice and suggests that ERα and ERβ play opposing roles in the brain.
- Published
- 2012
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26. Muscarinic mechanisms in psychotic disorders.
- Author
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McKinzie DL and Bymaster FP
- Subjects
- Animals, Antipsychotic Agents pharmacology, Cognition, Genome-Wide Association Study, Humans, Muscarinic Agonists therapeutic use, Psychotic Disorders drug therapy, Receptors, Muscarinic analysis, Receptors, Muscarinic drug effects, Receptors, Muscarinic genetics, Psychotic Disorders etiology, Receptors, Muscarinic physiology
- Abstract
Schizophrenia is a devastating disease with several broad symptom clusters and the current monoamine-based treatments do not adequately treat the disease, especially negative and cognitive symptoms. A proposed alternative approach for treating schizophrenia is through the use of compounds that activate certain muscarinic receptor subtypes, the so-called muscarinic cholinergic hypothesis theory. This theory has been revitalized with a number of recent and provocative findings including postmortem reports in schizophrenia patients showing decreased numbers of muscarinic M(1) and M(4) receptors in brain regions associated with schizophrenia as well as decreased muscarinic receptors in an in vivo imaging study. Studies with M(4) knockout mice have shown that there is a reciprocal relationship between M(4) and dopamine receptor function, and a number of muscarinic agonists have shown antidopaminergic activity in a variety of preclinical assays predictive of antipsychotic efficacy in the clinic. Furthermore, the M(1)/M(4) preferring partial agonist xanomeline has been shown to have antipsychotic-like and pro-cognitive activity in preclinical models and in clinical trials to decrease psychotic-like behaviors in Alzheimer's patients and positive, negative, and cognitive symptoms in patients with schizophrenia. Therefore, we propose that an agonist with M(1) and M(4) interactions would effectively treat core symptom clusters associated with schizophrenia. Currently, research is focused on developing subtype-selective muscarinic agonists and positive allosteric modulators that have reduced propensity for parasympathetic side-effects, but retain the therapeutic benefit observed with their less selective predecessors.
- Published
- 2012
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27. Discovery of aminobenzyloxyarylamides as κ opioid receptor selective antagonists: application to preclinical development of a κ opioid receptor antagonist receptor occupancy tracer.
- Author
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Mitch CH, Quimby SJ, Diaz N, Pedregal C, de la Torre MG, Jimenez A, Shi Q, Canada EJ, Kahl SD, Statnick MA, McKinzie DL, Benesh DR, Rash KS, and Barth VN
- Subjects
- Animals, Benzamides chemistry, Benzamides pharmacology, Brain metabolism, CHO Cells, Chromatography, Liquid, Cricetinae, Cricetulus, HEK293 Cells, Humans, Pyrrolidines chemistry, Pyrrolidines pharmacology, Radioligand Assay, Rats, Receptors, Opioid, kappa metabolism, Stereoisomerism, Structure-Activity Relationship, Tandem Mass Spectrometry, Benzamides chemical synthesis, Pyrrolidines chemical synthesis, Receptors, Opioid, kappa antagonists & inhibitors
- Abstract
Arylphenylpyrrolidinylmethylphenoxybenzamides were found to have high affinity and selectivity for κ opioid receptors. On the basis of receptor binding assays in Chinese hamster ovary (CHO) cells expressing cloned human opioid receptors, (S)-3-fluoro-4-(4-((2-(3-fluorophenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (25) had a K(i) = 0.565 nM for κ opioid receptor binding while having a K(i) = 35.8 nM for μ opioid receptors and a K(i) = 211 nM for δ opioid receptor binding. Compound 25 was also a potent antagonist of κ opioid receptors when tested in vitro using a [(35)S]-guanosine 5'O-[3-thiotriphosphate] ([(35)S]GTP-γ-S) functional assay in CHO cells expressing cloned human opioid receptors. Compounds were also evaluated for potential use as receptor occupancy tracers. Tracer evaluation was done in vivo, using liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods, precluding the need for radiolabeling. (S)-3-Chloro-4-(4-((2-(pyridine-3-yl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (18) was found to have favorable properties for a tracer for receptor occupancy, including good specific versus nonspecific binding and good brain uptake.
- Published
- 2011
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28. Lu AE58054, a 5-HT6 antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats.
- Author
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Arnt J, Bang-Andersen B, Grayson B, Bymaster FP, Cohen MP, DeLapp NW, Giethlen B, Kreilgaard M, McKinzie DL, Neill JC, Nelson DL, Nielsen SM, Poulsen MN, Schaus JM, and Witten LM
- Subjects
- Animals, Benzylamines metabolism, Cells, Cultured, Cognition Disorders chemically induced, Cricetinae, Dose-Response Relationship, Drug, HEK293 Cells, Humans, Indoles metabolism, Male, Phencyclidine administration & dosage, Rats, Rats, Sprague-Dawley, Recognition, Psychology drug effects, Serotonin Antagonists chemistry, Serotonin Antagonists metabolism, Benzylamines chemistry, Benzylamines therapeutic use, Cognition Disorders drug therapy, Cognition Disorders metabolism, Indoles chemistry, Indoles therapeutic use, Phencyclidine toxicity, Receptors, Serotonin metabolism, Recognition, Psychology physiology, Serotonin Antagonists therapeutic use
- Abstract
The in-vitro potency and selectivity, in-vivo binding affinity and effect of the 5-HT(6)R antagonist Lu AE58054 ([2-(6-fluoro-1H-indol-3-yl)-ethyl]-[3-(2,2,3,3-tetrafluoropropoxy)-benzyl]-amine) on impaired cognition were evaluated. Lu AE58054 displayed high affinity to the human 5-HT(6) receptor (5-HT(6)R) with a Ki of 0.83 nm. In a 5-HT(6) GTPgammaS efficacy assay Lu AE58054 showed no agonist activity, but demonstrated potent inhibition of 5-HT-mediated activation. Besides medium affinity to adrenergic alpha(1A)- and alpha(1B)-adrenoreceptors, Lu AE58054 demonstrated >50-fold selectivity for more than 70 targets examined. Orally administered Lu AE58054 potently inhibited striatal in-vivo binding of the 5-HT(6) antagonist radioligand [(3)H]Lu AE60157 ([(3)H]8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline), with an ED(50) of 2.7 mg/kg. Steady-state modelling of an acute pharmacokinetic/5-HT(6)R occupancy time-course experiment indicated a plasma EC(50) value of 20 ng/ml. Administration of Lu AE58054 in a dose range (5-20 mg/kg p.o.) leading to above 65% striatal 5-HT(6)R binding occupancy in vivo, reversed cognitive impairment in a rat novel object recognition task induced after subchronic treatment for 7 d with phencyclidine (PCP 2 mg/kg b.i.d., i.p. for 7 d, followed by 7 d drug free). The results indicate that Lu AE58054 is a selective antagonist of 5-HT(6)Rs with good oral bioavailability and robust efficacy in a rat model of cognitive impairment in schizophrenia. Lu AE58054 may be useful for the pharmacotherapy of cognitive dysfunction in disease states such as schizophrenia and Alzheimer's disease.
- Published
- 2010
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29. The Orexin-1 Receptor Antagonist SB-334867 Reduces Alcohol Relapse Drinking, but not Alcohol-Seeking, in Alcohol-Preferring (P) Rats.
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Dhaher R, Hauser SR, Getachew B, Bell RL, McBride WJ, McKinzie DL, and Rodd ZA
- Abstract
Principle: The orexin system has been hypothesized to regulate drug-seeking and drug self-administration behaviors, including ethanol (EtOH) seeking and consumption. However, studies on the effects of orexin receptor antagonists have not been conducted on robust alcohol-relapse behavior., Objectives: This study assessed the effects of the orexin-1 receptor antagonist, SB-334867, on alcohol-seeking behavior and responding for alcohol under relapse conditions., Methods: Adult alcohol-preferring (P) rats self-trained in 2-lever operant chambers to administer 15% EtOH (vol/vol) on a fixed-ratio-5 and water on a fixed-ratio-1 schedule of reinforcement. After 10 weeks, rats underwent extinction training for 7 sessions. Animals were then maintained in their home cages for 2 weeks before being tested for Pavlovian Spontaneous Recovery (PSR; a measure of alcohol seeking) for 4 sessions. Rats were then allowed a week in their home cages before being returned to the operant chamber with access to EtOH and water (relapse). Thirty minutes before the PSR and relapse test sessions, rats received 0, 10, or 20 mg/kg SB-334867., Results: Responses on the EtOH lever during the 1st PSR test session were ~70 presses/session (3-fold higher than baseline); SB-334867 did not alter responses on the EtOH lever. Under relapse conditions, P rats increased responding on the EtOH lever from 250 (at baseline) to 350 responses/session; both doses of SD-334867 prevented this increase., Conclusions: The results of this study suggest that activation of orexin-1 receptors is not involved in intrinsically initiated EtOH seeking, but may regulate the consummatory behavior of EtOH consumption.
- Published
- 2010
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30. Molecular mechanisms of action and in vivo validation of an M4 muscarinic acetylcholine receptor allosteric modulator with potential antipsychotic properties.
- Author
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Leach K, Loiacono RE, Felder CC, McKinzie DL, Mogg A, Shaw DB, Sexton PM, and Christopoulos A
- Subjects
- Acetylcholine pharmacology, Allosteric Regulation drug effects, Allosteric Regulation physiology, Allosteric Site drug effects, Allosteric Site physiology, Animals, Antipsychotic Agents chemistry, Avoidance Learning drug effects, Avoidance Learning physiology, Cell Line, Corpus Striatum drug effects, Corpus Striatum metabolism, Cricetinae, Cricetulus, Dose-Response Relationship, Drug, Guanosine 5'-O-(3-Thiotriphosphate) metabolism, In Vitro Techniques, Mice, Mice, Knockout, Models, Molecular, Multivariate Analysis, Muscarinic Antagonists pharmacokinetics, N-Methylscopolamine pharmacokinetics, Nicotinic Acids chemistry, Nicotinic Acids pharmacology, Parasympatholytics pharmacokinetics, Phosphorylation drug effects, Protein Transport drug effects, Quinuclidinyl Benzilate pharmacokinetics, Radioligand Assay methods, Rats, Receptor, Muscarinic M4 chemistry, Receptor, Muscarinic M4 deficiency, Receptor, Muscarinic M4 drug effects, Signal Transduction drug effects, Signal Transduction physiology, Thiophenes chemistry, Thiophenes pharmacology, Tritium metabolism, Tritium pharmacokinetics, Acetylcholine metabolism, Antipsychotic Agents pharmacology, Binding, Competitive drug effects, Receptor, Muscarinic M4 physiology
- Abstract
We recently identified LY2033298 as a novel allosteric potentiator of acetylcholine (ACh) at the M(4) muscarinic acetylcholine receptor (mAChR). This study characterized the molecular mode of action of this modulator in both recombinant and native systems. Radioligand-binding studies revealed that LY2033298 displayed a preference for the active state of the M(4) mAChR, manifested as a potentiation in the binding affinity of ACh (but not antagonists) and an increase in the proportion of high-affinity agonist-receptor complexes. This property accounted for the robust allosteric agonism displayed by the modulator in recombinant cells in assays of [(35)S]GTPgammaS binding, extracellular regulated kinase 1/2 phosphorylation, glycogen synthase kinase 3beta phosphorylation, and receptor internalization. We also found that the extent of modulation by LY2033298 differed depending on the signaling pathway, indicating that LY2033298 engenders functional selectivity in the actions of ACh. This property was retained in NG108-15 cells, which natively express rodent M(4) mAChRs. Functional interaction studies between LY2033298 and various orthosteric and allosteric ligands revealed that its site of action overlaps with the allosteric site used by prototypical mAChR modulators. Importantly, LY2033298 reduced [(3)H]ACh release from rat striatal slices, indicating retention of its ability to allosterically potentiate endogenous ACh in situ. Moreover, its ability to potentiate oxotremorine-mediated inhibition of condition avoidance responding in rodents was significantly attenuated in M(4) mAChR knockout mice, validating the M(4) mAChR as a key target of action of this novel allosteric ligand.
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- 2010
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31. In vitro and in vivo evidence for a lack of interaction with dopamine D2 receptors by the metabotropic glutamate 2/3 receptor agonists 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicaroxylate monohydrate (LY354740) and (-)-2-oxa-4-aminobicyclo[3.1.0] Hexane-4,6-dicarboxylic acid (LY379268).
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Fell MJ, Perry KW, Falcone JF, Johnson BG, Barth VN, Rash KS, Lucaites VL, Threlkeld PG, Monn JA, McKinzie DL, Marek GJ, Svensson KA, and Nelson DL
- Subjects
- Animals, Binding, Competitive, CHO Cells, Cell Membrane metabolism, Cricetinae, Cricetulus, Domperidone pharmacology, Dopamine biosynthesis, Dopamine D2 Receptor Antagonists, Female, Humans, Male, Mice, Mice, Knockout, Motor Activity drug effects, Protein Binding, Raclopride pharmacology, Radioligand Assay, Rats, Rats, Sprague-Dawley, Receptors, Dopamine D2 agonists, Receptors, Dopamine D2 genetics, Transfection, Amino Acids pharmacology, Bridged Bicyclo Compounds pharmacology, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Cell Membrane drug effects, Receptors, Dopamine D2 metabolism, Receptors, Metabotropic Glutamate agonists
- Abstract
Some recently published in vitro studies with two metabotropic glutamate 2/3 receptor (mGluR(2/3)) agonists [(-)-2-oxa-4-aminobicyclo[3.1.0] hexane-4,6-dicarboxylic acid (LY379268) and 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicaroxylate monohydrate (LY354740)] suggest that these compounds may also directly interact with dopamine (DA) D(2) receptors. The current in vitro and in vivo studies were undertaken to further explore this potential interaction with D(2) receptors. LY379268 and LY354740 failed to inhibit D(2) binding in both native striatal tissue homogenates and cloned receptors at concentrations up to 10 microM. LY379268 and LY354740 (up to 10 microM) also failed to stimulate [(35)S]GTPgammaS binding in D(2L)- and D(2S)-expressing clones in the presence of NaCl or N-methyl-d-glucamine. In an in vivo striatal D(2) receptor occupancy assay, LY379268 (3-30 mg/kg) or LY354740 (1-10 mg/kg) failed to displace raclopride (3 microg/kg i.v.), whereas aripiprazole (10-60 mg/kg) showed up to 90% striatal D(2) receptor occupancy. LY379268 (10 mg/kg) and raclopride (3 mg/kg) blocked d-amphetamine and phencyclidine (PCP)-induced hyperactivity in wild-type mice. However, the effects of LY379268 were lost in mGlu(2/3) receptor knockout mice. In DA D(2) receptor-deficient mice, LY379268 but not raclopride blocked both PCP and d-amphetamine-evoked hyperactivity. In the striatum and nucleus accumbens, LY379268 (3 and 10 mg/kg) was without effect on the DA synthesis rate in reserpinized rats and also failed to prevent S-(-)-3-(3-hydroxyphenyl)-N-propylpiperidine-induced reductions in DA synthesis rate. Taken together, the current data fail to show evidence of direct DA D(2) receptor interactions of LY379268 and LY354740 in vitro or in vivo. Instead, these results provide further evidence for a novel antipsychotic mechanism of action for mGluR(2/3) agonists.
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- 2009
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32. Autonomic activation associated with ethanol self-administration in adult female P rats.
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Bell RL, Rodd ZA, Toalston JE, McKinzie DL, Lumeng L, Li TK, McBride WJ, and Murphy JM
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- Animals, Body Weight physiology, Cues, Drinking physiology, Extinction, Psychological drug effects, Female, Heart Rate drug effects, Motor Activity drug effects, Motor Activity physiology, Rats, Telemetry, Water Deprivation physiology, Alcohol Drinking psychology, Central Nervous System Depressants pharmacology, Ethanol pharmacology
- Abstract
The present study examined changes in heart rate (HR) prior to and during limited access ethanol drinking in adult female P rats. P rats were implanted with radio-telemetric transmitters to measure HR. Daily testing involved a 90-min pre-test period (water only available) and a subsequent 90-min test period [either water (W) or ethanol available]. After a week of habituation, one ethanol group had access to ethanol for 7 weeks (CE), and another ethanol group had access for 4 weeks, was deprived for 2 weeks and then had access for a final week (DEP). Analyses of HR revealed that CE and DEP rats had significantly higher HR than W rats during test periods that ethanol was present and that DEP rats displayed higher HR during the early test period of the ethanol deprivation interval, as well. These data indicate that ethanol drinking induces HR activation in adult female P rats, and that this activation can be conditioned to the test cage environment, paralleling reports on contextual conditioning and cue-reactivity in alcoholics exposed to alcohol-associated stimuli. Therefore, this behavioral test may prove advantageous in screening pharmacotherapies for reducing craving and relapse, which are associated with cue-reactivity in abstinent alcoholics.
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- 2008
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33. Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia.
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Chan WY, McKinzie DL, Bose S, Mitchell SN, Witkin JM, Thompson RC, Christopoulos A, Lazareno S, Birdsall NJ, Bymaster FP, and Felder CC
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- Allosteric Regulation drug effects, Antipsychotic Agents therapeutic use, Cell Line, DNA Mutational Analysis, Humans, Nicotinic Acids pharmacology, Radioligand Assay, Receptor, Muscarinic M4 genetics, Signal Transduction drug effects, Small Molecule Libraries, Antipsychotic Agents pharmacology, Receptor, Muscarinic M4 metabolism, Schizophrenia drug therapy, Thiophenes pharmacology
- Abstract
Current antipsychotics provide symptomatic relief for patients suffering from schizophrenia and related psychoses; however, their effectiveness is variable and many patients discontinue treatment due to side effects. Although the etiology of schizophrenia is still unclear, a leading hypothesis implicates an imbalanced dopaminergic system. Muscarinic acetylcholine (ACh) receptors regulate dopamine levels in key areas of the brain involved in psychosis, with the M(4) subtype emerging as a key regulator of dopaminergic hyperactivity. Unfortunately, no selective small molecule tools exist to provide pharmacological validation of this hypothesis. Here, we describe the discovery of a small molecule modulator, LY2033298, that is highly selective for human M(4) receptors by virtue of targeting an allosteric site on this receptor. Pharmacological assays confirmed the selectivity of LY2033298 for the M(4) receptor and revealed the highest degree of positive allosteric enhancement of ACh potency thus far identified. Radioligand binding assays also show this compound to directly potentiate agonist binding while having minimal effects on antagonist binding. Mutational analysis identified a key amino acid (D(432)) in the third extracellular loop of the human M(4) receptor to be critical for selectivity and agonist potentiation by LY2033298. Importantly, LY2033298 was active in animal models predictive of clinical antipsychotic drug efficacy indicating its potential use as a first-in-class, selective, allosteric muscarinic antipsychotic agent.
- Published
- 2008
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34. Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia.
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Shekhar A, Potter WZ, Lightfoot J, Lienemann J, Dubé S, Mallinckrodt C, Bymaster FP, McKinzie DL, and Felder CC
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- Adolescent, Adult, Affect, Brief Psychiatric Rating Scale, Cognition Disorders diagnosis, Cognition Disorders epidemiology, Demography, Double-Blind Method, Female, Humans, Male, Middle Aged, Muscarinic Agonists adverse effects, Neuropsychological Tests, Pyridines adverse effects, Receptors, Cholinergic drug effects, Schizophrenia epidemiology, Severity of Illness Index, Thiadiazoles adverse effects, Muscarinic Agonists pharmacology, Muscarinic Agonists therapeutic use, Pyridines pharmacology, Pyridines therapeutic use, Receptors, Muscarinic drug effects, Schizophrenia drug therapy, Thiadiazoles pharmacology, Thiadiazoles therapeutic use
- Abstract
Objective: There are significant unmet needs in the treatment of schizophrenia, especially for the treatment of cognitive impairment, negative syndrome, and cognitive function. Preclinical data suggest that agonists with selective affinity for acetylcholine muscarinic receptors provide a potentially new mechanism to treat schizophrenia. The authors studied xanomeline, a relatively selective muscarinic type 1 and type 4 (M(1) and M(4)) receptor agonist, to determine if this agent is effective in the treatment of schizophrenia., Method: In this pilot study, the authors examined the efficacy of xanomeline on clinical outcomes in subjects with schizophrenia (N=20) utilizing a double-blind, placebo-controlled, 4-week treatment design. Outcome measures included the Positive and Negative Syndrome Scale (PANSS) for schizophrenia, the Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impression (CGI) scale, and a test battery designed to measure cognitive function in patients with schizophrenia., Results: Subjects treated with xanomeline did significantly better than subjects in the placebo group on total BPRS scores and total PANSS scores. In the cognitive test battery, subjects in the xanomeline group showed improvements most robustly in measures of verbal learning and short-term memory function., Conclusions: These results support further investigation of xanomeline as a novel approach to treating schizophrenia.
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- 2008
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35. Effects of kappa opioid receptor agonists on attention as assessed by a 5-choice serial reaction time task in rats.
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Shannon HE, Eberle EL, Mitch CH, McKinzie DL, and Statnick MA
- Subjects
- Analysis of Variance, Animals, Behavior, Animal drug effects, Dose-Response Relationship, Drug, Male, Naltrexone pharmacology, Narcotic Antagonists pharmacology, Photic Stimulation, Rats, Rats, Sprague-Dawley, Receptors, Opioid, kappa metabolism, Analgesics pharmacology, Attention drug effects, Choice Behavior drug effects, Reaction Time drug effects, Receptors, Opioid, kappa agonists
- Abstract
In humans, kappa opioid receptor agonists produce, among other effects, sedation and difficulty concentrating, suggesting that they may disrupt attention. The purpose of the present studies was therefore to evaluate the effects of kappa opioid receptor agonists on attention as assessed by a 5-choice serial reaction time task in rats. The kappa opioid receptor agonists (+)-U69,593 (0.1-0.56mg/kg), (+/-)-U50,488 (1.0-5.6mg/kg) and racemic GR89,696 (0.0003-0.01mg/kg) all produced dose-related decreases in the percentage of trials terminated by a correct or incorrect response and increases in the percentage of omissions. In contrast, the peripherally restricted opioid agonist ICI-204,448 was ineffective (1.0-10mg/kg). Moreover, the effects of GR89,696 were stereoselective in that (R)-GR89,696 was approximately equipotent to racemic GR89,696 and approximately 100-fold more potent than (S)-GR89,696. The opioid receptor antagonist naltrexone (0.3-3mg/kg) administered alone had no effects on performance. However, naltrexone, over the dose-range of 0.03-1.0mg/kg, produced a dose-related antagonism of the disruption produced by U69,593 (0.56mg/kg). In contrast, naltrexone, over the dose-range of 0.01-0.3mg/kg produced a dose-related antagonism of morphine (5.6mg/kg). Recent evidence has suggested that kappa opioid receptor agonists decrease dopaminergic and noradrenergic neurotransmission in prefrontal cortex and locus coeruleus. Together with previous findings, the present data indicate that kappa opioid receptor agonists disrupt performance of this attention task by decreasing the probability of responding by specific actions at central kappa opioid receptors, perhaps by decreasing dopaminergic and noradrenergic neurotransmission.
- Published
- 2007
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36. In vivo pharmacological characterization of the structurally novel, potent, selective mGlu2/3 receptor agonist LY404039 in animal models of psychiatric disorders.
- Author
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Rorick-Kehn LM, Johnson BG, Knitowski KM, Salhoff CR, Witkin JM, Perry KW, Griffey KI, Tizzano JP, Monn JA, McKinzie DL, and Schoepp DD
- Subjects
- Amino Acids pharmacology, Amphetamine pharmacology, Animals, Bridged Bicyclo Compounds, Heterocyclic chemistry, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Cyclic S-Oxides chemistry, Cyclic S-Oxides therapeutic use, Diazepam pharmacology, Disease Models, Animal, Dose-Response Relationship, Drug, Male, Mental Disorders psychology, Mice, Molecular Structure, Motor Activity drug effects, Phencyclidine pharmacology, Prefrontal Cortex drug effects, Prefrontal Cortex metabolism, Rats, Rats, Inbred F344, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate antagonists & inhibitors, Xanthenes pharmacology, Behavior, Animal drug effects, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Cyclic S-Oxides pharmacology, Mental Disorders drug therapy, Receptors, Metabotropic Glutamate agonists
- Abstract
Rationale: Data from both preclinical and clinical studies have provided proof of concept that modulation of limbic and forebrain glutamate, via mGlu2/3 receptor agonists, might provide therapeutic benefits in many psychiatric disorders including schizophrenia and anxiety., Objective: The aim of this study was to assess the efficacy of a structurally novel, potent, selective mGlu2/3 receptor agonist with improved bioavailability (LY404039) in animal models predictive of antipsychotic and anxiolytic efficacy., Materials and Methods: LY404039 was assessed in amphetamine- and phencyclidine-induced hyperlocomotion, conditioned avoidance responding, fear-potentiated startle, marble burying, and rotarod behavioral tests. Monoamine release and turnover were assessed using microdialysis and ex vivo tissue levels., Results: LY404039 attenuated amphetamine- and phencyclidine-induced hyperlocomotion (3-30 and 10 mg/kg, respectively). LY404039 (3-10 mg/kg) inhibited conditioned avoidance responding. LY404039 also reduced fear-potentiated startle in rats (3-30 microg/kg) and marble burying in mice (3-10 mg/kg), indicating anxiolytic-like effects. Importantly, LY404039 did not produce sedative effects or motor impairment as measured by rotarod performance and lack of escape failures in the conditioned avoidance task (at doses up to 30 and 10 mg/kg, respectively). LY404039 (10 mg/kg) also increased dopamine and serotonin release/turnover in the prefrontal cortex., Conclusions: These results demonstrate the broad preclinical efficacy of LY404039 across multiple animal models of antipsychotic and anxiolytic efficacy. Additionally, this compound modulates mesocortical neurotransmission and provides a novel mechanism for the treatment of psychiatric disorders that may be associated with improved efficacy and reduced incidence of undesirable side effects. As glutamatergic dysfunction has been linked to the etiology of schizophrenia, clinical studies with more potent mGlu2/3 agonists, such as LY404039, may be useful to explore the validity of this hypothesis.
- Published
- 2007
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37. Pharmacological and pharmacokinetic properties of a structurally novel, potent, and selective metabotropic glutamate 2/3 receptor agonist: in vitro characterization of agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid (LY404039).
- Author
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Rorick-Kehn LM, Johnson BG, Burkey JL, Wright RA, Calligaro DO, Marek GJ, Nisenbaum ES, Catlow JT, Kingston AE, Giera DD, Herin MF, Monn JA, McKinzie DL, and Schoepp DD
- Subjects
- Animals, Binding Sites, Bridged Bicyclo Compounds chemistry, Bridged Bicyclo Compounds pharmacokinetics, Bridged Bicyclo Compounds pharmacology, Bridged Bicyclo Compounds, Heterocyclic chemistry, Cell Line, Cerebral Cortex drug effects, Colforsin pharmacology, Cyclic AMP biosynthesis, Cyclic S-Oxides chemistry, Electric Stimulation, Excitatory Amino Acid Agonists chemistry, Excitatory Postsynaptic Potentials drug effects, Humans, Hydrolysis, In Vitro Techniques, Male, Phosphatidylinositols metabolism, Rats, Rats, Inbred F344, Rats, Sprague-Dawley, Serotonin pharmacology, Serotonin Antagonists pharmacology, Bridged Bicyclo Compounds, Heterocyclic pharmacokinetics, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Cyclic S-Oxides pharmacokinetics, Cyclic S-Oxides pharmacology, Excitatory Amino Acid Agonists pharmacokinetics, Excitatory Amino Acid Agonists pharmacology, Receptors, Metabotropic Glutamate drug effects
- Abstract
Group II metabotropic glutamate (mGlu) receptor agonists, including (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740) and (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), have demonstrated efficacy in animal models of anxiety and schizophrenia, and LY354740 decreased anxiety in human subjects. Herein, we report the in vitro pharmacological profile and pharmacokinetic properties of another potent, selective, and structurally novel mGlu2/3 receptor agonist, (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039) and provide comparisons with LY354740. Similar to LY354740, LY404039 is a nanomolar potent agonist at recombinant human mGlu2 and mGlu3 receptors (K(i) = 149 and 92, respectively) and in rat neurons expressing native mGlu2/3 receptors (Ki = 88). LY404039 is highly selective for mGlu2/3 receptors, showing more than 100-fold selectivity for these receptors, versus ionotropic glutamate receptors, glutamate transporters, and other receptors targeted by known anxiolytic and antipsychotic medications. Functionally, LY404039 potently inhibited forskolin-stimulated cAMP formation in cells expressing human mGlu2 and mGlu3 receptors. Electrophysiological studies indicated that LY404039 suppressed electrically evoked excitatory activity in the striatum, and serotonin-induced l-glutamate release in the prefrontal cortex; effects reversed by LY341495. These characteristics suggest LY404039 modulates glutamatergic activity in limbic and forebrain areas relevant to psychiatric disorders; and that, similar to LY354740, it works through a mechanism that may be devoid of negative side effects associated with current antipsychotics and anxiolytics. Interestingly, despite the slightly lower potency (approximately 2-5-fold) of LY404039 versus LY354740 in binding, functional, and electrophysiological assays, LY404039 demonstrated higher plasma exposure and better oral bioavailability in pharmacokinetic experiments. Collectively, the current data indicate that LY404039 may be valuable in the treatment of neuropsychiatric disorders, including anxiety and psychosis.
- Published
- 2007
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38. The metabotropic glutamate 2/3 receptor agonist LY404039 reduces alcohol-seeking but not alcohol self-administration in alcohol-preferring (P) rats.
- Author
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Rodd ZA, McKinzie DL, Bell RL, McQueen VK, Murphy JM, Schoepp DD, and McBride WJ
- Subjects
- Analysis of Variance, Animals, Appetitive Behavior drug effects, Conditioning, Operant drug effects, Dose-Response Relationship, Drug, Drug Administration Schedule, Excitatory Amino Acid Agonists administration & dosage, Female, Male, Random Allocation, Rats, Reaction Time drug effects, Reaction Time physiology, Receptors, Metabotropic Glutamate agonists, Reinforcement, Psychology, Alcohol Drinking physiopathology, Appetitive Behavior physiology, Conditioning, Operant physiology, Extinction, Psychological physiology, Receptors, Metabotropic Glutamate physiology, Self Administration
- Abstract
Metabotropic glutamate (mGlu) receptors have been shown to mediate a number of behaviors including emotionality and responsivity to stress as demonstrated by efficacy in preclinical and clinical studies. The objective of this study was to assess the effects of the mGlu2/3 receptor agonist LY404039 (LY) on operant ethanol (EtOH) self-administration during alcohol seeking (pavlovian spontaneous recovery, PSR), alcohol relapse (alcohol deprivation effect, ADE), and maintenance responding for alcohol. Adult alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) and water on a concurrent fixed-ratio 5-fixed-ratio 1 (FR5-FR1) schedule of reinforcement in daily 1h sessions. After at least 10 weeks of daily 1 h sessions, rats underwent seven extinction sessions, followed by 2 weeks of no manipulation, and then rats were tested for the expression of an EtOH PSR for four sessions. Rats were then given a week in their home cage before being returned to the operant chambers with access to EtOH and water (alcohol relapse). Finally, the effects of LY upon maintenance EtOH and water responding were assessed once stable responding was reestablished. The mGlu2/3 receptor agonist LY404039 reduced responding on the EtOH in the PSR test. LY also reduced the expression of an alcohol deprivation effect (ADE) during relapse, but did not reduce EtOH responding under maintenance conditions. The results of this study demonstrate that activating mGlu2/3 receptors inhibits the expression of alcohol seeking and relapse behavior without altering alcohol self-administration behavior.
- Published
- 2006
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39. Melanin-concentrating hormone-1 receptor modulates neuroendocrine, behavioral, and corticolimbic neurochemical stress responses in mice.
- Author
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Smith DG, Davis RJ, Rorick-Kehn L, Morin M, Witkin JM, McKinzie DL, Nomikos GG, and Gehlert DR
- Subjects
- Acetylcholine metabolism, Adrenocorticotropic Hormone blood, Alprazolam pharmacology, Animals, Anti-Anxiety Agents pharmacology, Behavior, Animal drug effects, Body Temperature drug effects, Brain Chemistry drug effects, Corticosterone blood, Dose-Response Relationship, Drug, Hypothalamic Hormones administration & dosage, Male, Maze Learning drug effects, Maze Learning physiology, Melanins administration & dosage, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurosecretory Systems drug effects, Pituitary Hormones administration & dosage, Random Allocation, Receptors, Somatostatin antagonists & inhibitors, Receptors, Somatostatin deficiency, Behavior, Animal physiology, Brain Chemistry physiology, Neurosecretory Systems metabolism, Receptors, Somatostatin physiology, Stress, Physiological metabolism, Stress, Physiological physiopathology, Stress, Physiological psychology
- Abstract
Repeated exposure to stressful conditions is linked to the etiology of affective disorders. The melanin-concentrating hormone-1 receptor (MCHR1) may be a novel mechanism that is involved in the modulation of stress responses and affective states. The role of MCHR1 in neuroendocrine, behavioral, and neurochemical stress, and anxiety-related responses was examined by monitoring the effects of melanin-concentrating hormone (MCH) and the selective MCHR1 antagonist, GW3430, in inbred C57Bl/6NTac and MCHR1-knockout (KO) and wild-type (WT) mice. Intracerebroventricular injection of MCH increased plasma corticosterone, and produced anxiety-related responses in the elevated plus maze. The selective MCHR1 antagonist, GW3430, blocked the neuroendocrine and behavioral effects of MCH and produced anxiolytic-like effects by itself in animal models of anxiety. Moreover, KO mice had an anxiolytic-like phenotype in behavioral models of anxiety, and GW3430 had anxiolytic-like effects in WT, but not KO mice. Lastly, stressor-evoked acetylcholine release within the prefrontal cortex of inbred and WT mice, but not KO mice, was blocked by GW3430. We show that MCH elicits anxiety-like responses and that the effects of a selective MCHR1 antagonist and the phenotype of KO mice are consistent with anxiolytic-like action. Distinct behavioral, physiological, and neurochemical stress, and anxiety-related responses were selectively modulated by the MCHR1, and these actions may involve corticolimbic regulation of stress responsivity and anxiety.
- Published
- 2006
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40. Procholinergic and memory enhancing properties of the selective norepinephrine uptake inhibitor atomoxetine.
- Author
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Tzavara ET, Bymaster FP, Overshiner CD, Davis RJ, Perry KW, Wolff M, McKinzie DL, Witkin JM, and Nomikos GG
- Subjects
- Acetylcholine metabolism, Animals, Atomoxetine Hydrochloride, Central Nervous System Stimulants pharmacology, Cerebral Cortex drug effects, Cerebral Cortex metabolism, Cholinergic Fibers metabolism, Hippocampus drug effects, Hippocampus metabolism, Male, Methylphenidate pharmacology, Microdialysis, Morpholines pharmacology, Norepinephrine metabolism, Rats, Rats, Sprague-Dawley, Rats, Wistar, Reboxetine, Receptors, Dopamine drug effects, Receptors, Dopamine metabolism, Adrenergic Uptake Inhibitors pharmacology, Cholinergic Fibers drug effects, Maze Learning drug effects, Pattern Recognition, Visual drug effects, Propylamines pharmacology
- Abstract
Atomoxetine has been approved by the FDA as the first new drug in 30 years for the treatment of attention deficit/hyperactivity disorder (ADHD). As a selective norepinephrine uptake inhibitor and a nonstimulant, atomoxetine has a different mechanism of action from the stimulant drugs used up to now for the treatment of ADHD. Since brain acetylcholine (ACh) has been associated with memory, attention and motivation, processes dysregulated in ADHD, we investigated the effects of atomoxetine on cholinergic neurotransmission. We showed here that, in rats, atomoxetine (0.3-3 mg/kg, i.p.),--increases in vivo extracellular levels of ACh in cortical but not subcortical brain regions. The marked increase of cortical ACh induced by atomoxetine was dependent upon norepinephrine alpha-1 and/or dopamine D1 receptor activation. We observed similar increases in cortical and hippocampal ACh release with methylphenidate (1 and 3 mg/kg, i.p.)--currently the most commonly prescribed medication for the treatment of ADHD--and with the norepinephrine uptake inhibitor reboxetine (3-30 mg/kg, i.p.). Since drugs that increase cholinergic neurotransmission are used in the treatment of cognitive dysfunction and dementias, we also investigated the effects of atomoxetine on memory tasks. We showed that, consistent with its cortical procholinergic and catecholamine-enhancing profile, atomoxetine (1-3 mg/kg, p.o.) significantly ameliorated performance in the object recognition test and the radial arm-maze test.
- Published
- 2006
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41. Improved bioavailability of the mGlu2/3 receptor agonist LY354740 using a prodrug strategy: in vivo pharmacology of LY544344.
- Author
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Rorick-Kehn LM, Perkins EJ, Knitowski KM, Hart JC, Johnson BG, Schoepp DD, and McKinzie DL
- Subjects
- Administration, Oral, Alanine analogs & derivatives, Alanine pharmacokinetics, Alanine pharmacology, Animals, Biological Availability, Body Temperature drug effects, Dose-Response Relationship, Drug, Male, Mice, Mice, Inbred DBA, Motor Activity drug effects, Rats, Rats, Sprague-Dawley, Stress, Physiological physiopathology, Time Factors, Behavior, Animal drug effects, Bridged Bicyclo Compounds pharmacokinetics, Bridged Bicyclo Compounds pharmacology, Prodrugs pharmacokinetics, Prodrugs pharmacology, Receptors, Metabotropic Glutamate agonists
- Abstract
Numerous studies have indicated that selective agonists of group II metabotropic glutamate (mGlu) receptors, such as LY354740 [(1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate] and LY379268 [(-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate], may be useful in the treatment of many psychiatric disorders, including psychosis, anxiety, and drug withdrawal. Although animal and human studies demonstrate potential therapeutic utility, poor oral bioavailability is a limiting factor in the clinical development of these compounds. Therefore, a novel prodrug approach is being pursued to increase exposure levels of active compound after oral administration. Here, we demonstrate a 10-fold increase in brain, plasma, and cerebrospinal fluid levels of LY354740 after oral prodrug administration. Furthermore, we compare the oral efficacy of the mGlu2/3 receptor agonist LY354740 and its prodrug LY544344 [(1S,2S,5R,6S)-2-[(2'S)-(2'-amino)propionyl]aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride] in rodent models of psychosis and anxiety. Phencyclidine (PCP)-induced hyperlocomotion was dose dependently inhibited in rats receiving oral administration of 30 or 100 mg/kg LY544344, whereas LY354740 did not significantly reverse PCP-mediated behaviors at doses up to 100 mg/kg. Orally administered LY544344 (30 mg/kg) and subcutaneously administered LY354740 (10 mg/kg) attenuated stress-induced hyperthermia in DBA/2 mice, with the prodrug producing anxiolytic effects at lower oral doses than the parent compound. Although oral administration of LY354740 did not significantly affect fear-induced suppression of operant responding in rats, subcutaneously administered LY354740 (10 or 20 mg/kg) and orally administered LY544344 (10 or 30 mg/kg) produced significant anxiolytic effects in this model. The present data confirm that mGlu2/3 receptor agonists produce antipsychotic and anxiolytic effects in animal behavioral models and demonstrate that oral bioavailability of LY354740 was substantially increased using a prodrug strategy.
- Published
- 2006
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42. Pharmacological characterization of stress-induced hyperthermia in DBA/2 mice using metabotropic and ionotropic glutamate receptor ligands.
- Author
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Rorick-Kehn LM, Hart JC, and McKinzie DL
- Subjects
- Analysis of Variance, Animals, Behavior, Animal drug effects, Body Temperature drug effects, Dose-Response Relationship, Drug, Fever etiology, Male, Mice, Mice, Inbred DBA, Stress, Physiological complications, Excitatory Amino Acid Agents pharmacology, Fever drug therapy, Ligands, Receptors, Kainic Acid physiology, Receptors, Metabotropic Glutamate physiology
- Abstract
Rationale: Accumulating evidence suggests that drugs acting on the glutamatergic system may represent promising novel therapeutic targets for the treatment of anxiety disorders. The stress-induced hyperthermia paradigm has been used widely to model some of the physiological symptoms associated with anxiety disorders and has produced results that are predictive of clinical efficacy. We have modified this paradigm to measure the autonomic consequences of stress induced by the fear of predation in mice., Objective: To evaluate the efficacy of several classes of metabotropic and ionotropic glutamate receptor ligands, as well as known anxiolytics and psychotropic comparators, in attenuating predatory-stress-induced hyperthermia., Methods: Male DBA/2 mice were implanted with radiotelemetric transmitters in the peritoneal cavity to measure stress-related increases in core body temperature, following placement in a novel cage containing soiled rat shavings., Results: Clinically active compounds such as chlordiazepoxide (5-10 mg/kg), alprazolam (0.3-3 mg/kg), and buspirone (10-30 mg/kg) exhibited an anxiolytic profile. Assessment of glutamatergic agents indicated that the mGlu1 receptor antagonist LY456236 (10-30 mg/kg), mGlu5 receptor antagonist MPEP (10-30 mg/kg), mGlu2/3 receptor agonist LY354740 (3-10 mg/kg), mGlu2 receptor potentiator LY566332 (30 and 100 mg/kg), mGlu8 receptor agonist (S)-3,4-dicarboxyphenylglycine (30-60 mg/kg), competitive NMDA receptor antagonist LY235959 (1 mg/kg), AMPA receptor antagonist GYKI-52466 (10-20 mg/kg), and glycine transporter-1 (GlyT-1) inhibitor ALX-5407 (3-10 mg/kg) dose-dependently attenuated stress-induced hyperthermia. The AMPA receptor potentiator LY451646, iGlu5 kainate receptor antagonist LY382884, glycine(B) receptor partial agonist D: -cycloserine, and GlyT-1 inhibitor ORG-24461 were ineffective in this model., Conclusion: Select metabotropic and ionotropic glutamate receptor ligands exhibited an anxiolytic profile, as measured by the attenuation of stress-induced hyperthermia, and may represent viable targets for the development of pharmacological treatments for anxiety-related disorders.
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- 2005
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43. Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s).
- Author
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Johnson MP, Barda D, Britton TC, Emkey R, Hornback WJ, Jagdmann GE, McKinzie DL, Nisenbaum ES, Tizzano JP, and Schoepp DD
- Subjects
- Animals, Cyclopropanes metabolism, Excitatory Postsynaptic Potentials drug effects, Glycine analogs & derivatives, Glycine metabolism, Humans, Male, Mice, Mice, Inbred DBA, Mice, Inbred ICR, Motor Activity drug effects, Phencyclidine pharmacology, Radioligand Assay, Rats, Rats, Sprague-Dawley, Receptors, Metabotropic Glutamate physiology, Anxiety drug therapy, Excitatory Amino Acid Agonists pharmacology, Psychotic Disorders drug therapy, Receptors, Metabotropic Glutamate agonists, Synaptic Transmission drug effects
- Abstract
Rationale: To increase subtype selectivity and provide a novel means to alter receptor function, we discovered and characterization potentiators for the metabotropic glutamate 2 receptor (mGlu2)., Methods and Results: A class of 3-pyridylmethylsulfonamides (e.g., 3-MPPTS; 2,2,2-trifluoro-N-[3-(2-methoxyphenoxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulfonamide) were found to be potent, subtype-selective potentiators of human and rat mGlu2. The sulfonamides increased agonist potency in functional assays but did not displace orthosteric radiolabeled antagonist or agonist binding to cloned mGlu2 receptors. Rather, the modulators increased the affinity of most of the orthosteric agonists including glutamate, DCG-IV (2S,2'R,3'R)-2-(2',3'-dicarboxylcyclopropyl)glycine), and LY354740 (1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicaroxylate monohydrate). In striatal brain slices, LY354740 inhibited evoked excitatory postsynaptic potentials (EPSPs) equally well following either a low- (0.06 Hz) or high (4 Hz)-frequency stimulation of corticostriatal afferents. In contrast, the mGlu2 potentiator cyPPTS (2,2,2-trifluoro-N-[3-(cyclopentyloxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulfonamide) inhibited striatal EPSPs only at higher frequencies of stimulation (2 and 4 Hz). Several sulfonamides including 4-MPPTS, 4-APPES (N-[4-(4-carboxamidophenoxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride monohydrate) and/or CBiPES N-[4'-cyano-biphenyl-3-yl)-N-(3-pyridinylmethyl)-ethanesulfonamide hydrochloride) were tested in mGlu2/3 agonist-sensitive rodent model(s) of anxiety and psychosis. As seen with LY354740, both 4-MPPTS and 4-APPES were efficacious in a rat fear-potentiated startle paradigm. Likewise in mice, CBiPES attenuated a stress-induced hyperthermia and PCP-induced hyperlocomotor activity. Furthermore, CBiPES mediated alteration in PCP-induced hyperlocomotor activity was sensitive to mGlu2/3 antagonist pretreatment., Conclusions: Taken together, the data indicate mGlu2 receptor potentiators have a unique use-dependent effect on presynaptic glutamate release, and show efficacy in several mGlu2/3-sensitive animal models of psychiatric disorders.
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- 2005
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44. Pharmacologic interactions between the muscarinic cholinergic and dopaminergic systems in the modulation of prepulse inhibition in rats.
- Author
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Jones CK, Eberle EL, Shaw DB, McKinzie DL, and Shannon HE
- Subjects
- Acoustic Stimulation, Animals, Apomorphine pharmacology, Benzazepines pharmacology, Dose-Response Relationship, Drug, Haloperidol pharmacology, Male, Rats, Rats, Sprague-Dawley, Cognition Disorders drug therapy, Receptors, Dopamine physiology, Receptors, Muscarinic physiology, Reflex drug effects, Reflex, Startle drug effects
- Abstract
Prepulse inhibition (PPI) of the acoustic startle reflex is a sensorimotor gating process known to be deficient in a number of neurologic and psychiatric conditions, including schizophrenia. Multiple lines of evidence have indicated that the dopaminergic and muscarinic cholinergic systems play an important role in modulating PPI. Moreover, interactions between the dopaminergic and muscarinic cholinergic systems are well known; however, little is known about potential interactions between the two systems in modulating PPI. Therefore, the purpose of the present studies was to determine whether interactions occur between the muscarinic cholinergic and dopaminergic systems in modulating PPI. The efficacy of muscarinic cholinergic receptor agonists in reversing the disruption of PPI induced by apomorphine, a D1/D2 dopamine receptor agonist, was evaluated in male Sprague-Dawley rats. The M1/M4-preferring muscarinic agonist xanomeline and the M2/M4-preferring agonist BuTAC [([5R-[exo]-6-[butylthio]-1,2,5-thiadiazol-3-yl-]-1-azabyciclo-[3.2.1])octane oxalate] reversed the apomorphine-induced disruption of PPI in a manner similar to that produced by the D2-like dopamine receptor antagonists haloperidol and olanzapine. The muscarinic agonists oxotremorine, RS86 [[2-ethyl-8-methyl-2,8-diazaspiro(4.5)decane-1,3-dione] hydrochloride], pilocarpine, milameline, and sabcomeline also reversed the apomorphine-induced disruption of PPI. Moreover, the muscarinic antagonist scopolamine also disrupted PPI, and the D2-like receptor antagonist haloperidol, but not the D1-like receptor antagonist SCH23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine], reversed the scopolamine-induced disruption. In addition, xanomeline produced a significant reversal of the disruption in PPI produced by scopolamine. Collectively, the present findings demonstrate that a functional interaction occurs between the muscarinic cholinergic and dopaminergic systems in modulating PPI and that muscarinic cholinergic agonists may be effective in the treatment of the PPI and other cognitive impairments observed in schizophrenia.
- Published
- 2005
- Full Text
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45. M4 muscarinic receptors regulate the dynamics of cholinergic and dopaminergic neurotransmission: relevance to the pathophysiology and treatment of related CNS pathologies.
- Author
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Tzavara ET, Bymaster FP, Davis RJ, Wade MR, Perry KW, Wess J, McKinzie DL, Felder C, and Nomikos GG
- Subjects
- Acetylcholine metabolism, Amphetamine pharmacology, Animals, Central Nervous System Diseases drug therapy, Central Nervous System Diseases metabolism, Dopamine metabolism, Gene Deletion, Homeostasis drug effects, Mesencephalon drug effects, Mesencephalon metabolism, Mice, Mice, Knockout, Models, Neurological, Nucleus Accumbens drug effects, Nucleus Accumbens metabolism, Receptor, Muscarinic M2 genetics, Receptor, Muscarinic M2 metabolism, Receptor, Muscarinic M4 genetics, Scopolamine pharmacology, Time Factors, Central Nervous System Diseases pathology, Central Nervous System Diseases physiopathology, Receptor, Muscarinic M4 metabolism, Synaptic Transmission drug effects
- Abstract
Dopaminergic dysfunction is an important pathogenetic factor for brain pathologies such as Parkinson's disease, ADHD, schizophrenia, and addiction as well as for metabolic disorders and anorexia. Dopaminergic neurons projecting from the midbrain to forebrain regions, such as the nucleus accumbens and the prefrontal cortex, regulate motor and cognitive functions and coordinate the patterned response of the organism to sensory, affective, and rewarding stimuli. In this study, we showed that dopaminergic neurotransmission is highly dependent on M4 cholinergic muscarinic receptor function. Using in vivo microdialysis, we found elevated dopamine (DA) basal values and enhanced DA response to psychostimulants in the nucleus accumbens of M4 knockout mice. We also demonstrated impaired homeostatic control of cholinergic activity that leads to increased basal acetylcholine efflux in the midbrain of these animals. Thus, loss of M4 muscarinic receptor control of cholinergic function effectuates a state of dopaminergic hyperexcitability. This may be responsible for pathological conditions, in which appetitive motivation as well as affective and cognitive processing is impaired. We propose that M4 receptor agonists could represent an innovative strategy for the treatment of pathologies associated with hyperdopaminergia.
- Published
- 2004
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46. Low-dose stimulatory effects of ethanol during adolescence in rat lines selectively bred for high alcohol intake.
- Author
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Rodd ZA, Bell RL, McKinzie DL, Webster AA, Murphy JM, Lumeng L, Li TK, and McBride WJ
- Subjects
- Age Factors, Alcohol Drinking genetics, Animals, Breeding methods, Dose-Response Relationship, Drug, Female, Male, Motor Activity genetics, Rats, Rats, Wistar, Species Specificity, Alcohol Drinking physiopathology, Ethanol administration & dosage, Motor Activity drug effects
- Abstract
Background: The low-dose stimulatory effect of ethanol (EtOH) in rats has been hypothesized to reflect its hedonic effects and to be associated with a genetic predisposition toward high alcohol preference. To test the hypothesis that phenotypes associated with high alcohol preference in adulthood are also present in adolescent rats at the time of onset of alcohol drinking, the current study examined the effects of EtOH on locomotor activity (LMA) during adolescence in lines of rats selectively bred for divergent alcohol intakes., Methods: Subjects were adolescent (31-40 days of age) rats from the alcohol-preferring (P) and -nonpreferring (NP) lines and from the high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) replicate lines. On day 1, all subjects (n = 8-10/line/gender/dose) received intraperitoneal saline injections and were placed in the activity monitor for 30 min. On day 2, subjects received intraperitoneal saline or 0.25, 0.50, 0.75, 1.0, or 1.5 g EtOH/kg., Results: The LMA of male and female P rats was increased with low doses (0.25-0.75 g/kg) and decreased at the highest dose (1.5 g/kg) of EtOH. Similar effects were observed with low doses of EtOH on the LMA of HAD-1 and HAD-2 rats. None of the EtOH doses stimulated LMA in the NP, LAD-1, or LAD-2 rats, although all of the low-alcohol-intake lines of rats showed decreased LMA at the highest dose of EtOH. Only the P rats among the high-alcohol-consuming lines of rats showed decreased LMA at the highest dose of EtOH., Conclusion: Selective breeding for high alcohol consumption seems to be associated with increased sensitivity to the low-dose stimulating effects of EtOH and reduced sensitivity to the high-dose motor-impairing effects of ethanol. The expression of these phenotypes emerges during adolescence by the age of onset of alcohol-drinking behavior.
- Published
- 2004
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47. Diverse psychotomimetics act through a common signaling pathway.
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Svenningsson P, Tzavara ET, Carruthers R, Rachleff I, Wattler S, Nehls M, McKinzie DL, Fienberg AA, Nomikos GG, and Greengard P
- Subjects
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine pharmacology, Animals, Brain drug effects, Corpus Striatum drug effects, Corpus Striatum metabolism, Cyclic AMP Response Element-Binding Protein metabolism, Dextroamphetamine pharmacology, Dopamine metabolism, Dopamine and cAMP-Regulated Phosphoprotein 32, Frontal Lobe drug effects, Frontal Lobe metabolism, Genes, fos, Glycogen Synthase Kinase 3 metabolism, Glycogen Synthase Kinase 3 beta, Lysergic Acid Diethylamide pharmacology, Male, Mice, Mice, Knockout, Motor Activity drug effects, Nerve Tissue Proteins metabolism, Phencyclidine pharmacology, Phosphoprotein Phosphatases antagonists & inhibitors, Phosphorylation, Protein Phosphatase 1, RNA, Messenger genetics, RNA, Messenger metabolism, Receptors, Dopamine D1 genetics, Receptors, Dopamine D1 metabolism, Reflex, Startle drug effects, Synaptic Transmission, Brain metabolism, Central Nervous System Agents pharmacology, Phosphoproteins metabolism, Signal Transduction
- Abstract
Three distinct classes of drugs: dopaminergic agonists (such as D-amphetamine), serotonergic agonists (such as LSD), and glutamatergic antagonists (such as PCP) all induce psychotomimetic states in experimental animals that closely resemble schizophrenia symptoms in humans. Here we implicate a common signaling pathway in mediating these effects. In this pathway, dopamine- and an adenosine 3',5'-monophosphate (cAMP)-regulated phospho-protein of 32 kilodaltons (DARPP-32) is phosphorylated or dephosphorylated at three sites, in a pattern predicted to cause a synergistic inhibition of protein phosphatase-1 and concomitant regulation of its downstream effector proteins glycogen synthesis kinase-3 (GSK-3), cAMP response element-binding protein (CREB), and c-Fos. In mice with a genetic deletion of DARPP-32 or with point mutations in phosphorylation sites of DARPP-32, the effects of D-amphetamine, LSD, and PCP on two behavioral parameters-sensorimotor gating and repetitive movements-were strongly attenuated.
- Published
- 2003
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- View/download PDF
48. Role for M5 muscarinic acetylcholine receptors in cocaine addiction.
- Author
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Fink-Jensen A, Fedorova I, Wörtwein G, Woldbye DP, Rasmussen T, Thomsen M, Bolwig TG, Knitowski KM, McKinzie DL, Yamada M, Wess J, and Basile A
- Subjects
- Animals, Avoidance Learning drug effects, Cocaine-Related Disorders genetics, Dose-Response Relationship, Drug, Male, Mice, Mice, Transgenic, Receptor, Muscarinic M5, Receptors, Muscarinic genetics, Self Administration, Substance Withdrawal Syndrome genetics, Avoidance Learning physiology, Cocaine administration & dosage, Cocaine-Related Disorders metabolism, Receptors, Muscarinic deficiency, Substance Withdrawal Syndrome metabolism
- Abstract
Muscarinic cholinergic receptors of the M5 subtype are expressed by dopamine-containing neurons of the ventral tegmentum. These M5 receptors modulate the activity of midbrain dopaminergic neurons, which play an important role in mediating reinforcing properties of abused psychostimulants like cocaine. The potential role of M5 receptors in the reinforcing effects of cocaine was investigated using M5 receptor-deficient mice in a model of acute cocaine self-administration. The M5-deficient mice self-administered cocaine at a significantly lower rate than wild-type controls. In the conditioned place preference procedure, a classic test for evaluating the rewarding properties of drugs, M5-deficient mice spent significantly less time in the cocaine-paired compartment than control mice. Moreover, the severity of the cocaine withdrawal syndrome (withdrawal-associated anxiety measured in the elevated plus-maze) was significantly attenuated in mice lacking the M5 receptor. These results demonstrate that M5 receptors play an important role in mediating both cocaine-associated reinforcement and withdrawal., (Copyright 2003 Wiley-Liss, Inc.)
- Published
- 2003
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49. Muscarinic mechanisms of antipsychotic atypicality.
- Author
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Bymaster FP, Felder CC, Tzavara E, Nomikos GG, Calligaro DO, and Mckinzie DL
- Subjects
- Acetylcholine metabolism, Animals, Antipsychotic Agents chemistry, Behavior drug effects, Binding, Competitive, Dose-Response Relationship, Drug, Drug Interactions, Humans, Kinetics, Models, Animal, Neural Inhibition drug effects, Receptors, Muscarinic classification, Receptors, Muscarinic drug effects, Second Messenger Systems drug effects, Antipsychotic Agents pharmacology, Antipsychotic Agents therapeutic use, Cholinergic Agents pharmacology, Psychotic Disorders drug therapy, Receptors, Muscarinic metabolism
- Abstract
The interactions of the atypical antipsychotic drugs (APD) clozapine, olanzapine, risperidone, quetiapine and ziprasidone with muscarinic receptors were reviewed. Only clozapine and olanzapine have marked affinity for muscarinic receptors in radioligand binding studies; however, the affinity of these compounds is considerably lower than classical muscarinic antagonists. Although functional assays in cell lines transfected with muscarinic receptors suggest that olanzapine and clozapine have weak partial agonist activity at muscarinic receptors, particularly M4 receptors, studies in vitro and in vivo indicate that the compounds function as antagonists. In animal studies and in humans, clozapine has pronounced antimuscarinic effects whereas olanzapine has weak antimuscarinic effects. However, olanzapine significantly occupies central muscarinic receptors in humans. Overall, the role of muscarinic receptors in the antipsychotic effects of clozapine and olanzapine is controversial and complex.
- Published
- 2003
- Full Text
- View/download PDF
50. Dysregulated hippocampal acetylcholine neurotransmission and impaired cognition in M2, M4 and M2/M4 muscarinic receptor knockout mice.
- Author
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Tzavara ET, Bymaster FP, Felder CC, Wade M, Gomeza J, Wess J, McKinzie DL, and Nomikos GG
- Subjects
- Animals, Avoidance Learning drug effects, Avoidance Learning physiology, Cognition physiology, Crosses, Genetic, Environment, Habituation, Psychophysiologic physiology, Hippocampus drug effects, Hippocampus physiology, Homeostasis, Male, Mice, Mice, Knockout, Microdialysis, Muscarinic Antagonists pharmacology, Receptor, Muscarinic M2 deficiency, Receptor, Muscarinic M2 drug effects, Receptor, Muscarinic M2 genetics, Receptor, Muscarinic M4 deficiency, Receptor, Muscarinic M4 drug effects, Receptor, Muscarinic M4 genetics, Scopolamine pharmacology, Synaptic Transmission drug effects, Synaptic Transmission physiology, Acetylcholine metabolism, Hippocampus metabolism, Receptor, Muscarinic M2 physiology, Receptor, Muscarinic M4 physiology
- Abstract
Among the five different muscarinic receptors that have been cloned and characterized, M2 and M4 receptors are localized both post- and presynaptically and are believed to have a pronounced autoreceptor role. The functional importance of these receptors in the regulation of acetylcholine release in the hippocampus and in cognitive processes was investigated by using M2 and M4 receptor single knockout (KO) as well as M2/M4 receptor double KO mice. We found profound alterations in acetylcholine homeostasis in the hippocampus of both M2- and M4-KO mice as well as of the combined M2/M4-KOs, as assessed by in vivo microdialysis. Basal acetylcholine efflux in the hippocampus was significantly increased in M4-KO and was elevated further in M2/M4-KOs. The increase in hippocampal acetylcholine induced by local administration of scopolamine was markedly reduced in M2-KO and completely abolished in M2/M4-KOs. In M2-KO and much more in M2/M4-KOs, the increase in hippocampal acetylcholine triggered by exposure to a novel environment was more pronounced both in amplitude and duration, with a similar trend observed for M4-KOs. Dysregulation of cholinergic function in the hippocampus, as it could result from perturbed autoreceptor function, may be associated with cognitive deficits. Importantly, M2- and M2/M4-KO, but not M4-KO, animals showed an impaired performance in the passive avoidance test. Together these results suggest a crucial role for muscarinic M2 and M4 receptors in the tonic and phasic regulation of acetylcholine efflux in the hippocampus as well as in cognitive processes.
- Published
- 2003
- Full Text
- View/download PDF
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