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Inadequate dietary magnesium (Mg) intake is a growing public health concern. Mg is critical for diverse metabolic processes including energy production, macromolecule biosynthesis, and electrolyte homeostasis. Inadequate free Mg2+ ion concentration ([Mg2+]) in the brain is associated with several neurological and behavioral disorders. Elevating [Mg2+]in the brain using oral Mg supplementation has proven to be challenging due to the tight regulation of Mg2+ transport to the brain. This study explored the effect of short-term moderate reduction in dietary Mg intake (87% of normal Mg diet for 30 days) on [Mg2+] in the cerebrospinal fluid (CSF) ([Mg2+]CSF) and red blood cells (RBCs) ([Mg2+]RBC) in adult male rats. In addition, we investigated the effectiveness of magnesium-rich blend of Swiss chard and buckwheat extracts (SC/BW extract) in increasing brain [Mg2+] compared to various Mg salts commonly used as dietary supplements. Animals were assigned to either normal or low Mg diet for 30 - 45 days. Following this, animals maintained on low Mg diet were supplemented with various Mg compounds. [Mg2+]CSF and [Mg2+]RBC were measured at baseline and following Mg administration. Anxiety-like behavior and cognitive function were also evaluated. The present study showed that a short-term and moderate reduction in Mg dietary intake results in a significant decline in [Mg2+]CSF and [Mg2+]RBC and the emergence of anxiety-like behavior in comparison to animals maintained on normal Mg diet. Supplementation with SC/BW extract significantly elevated [Mg2+]CSF and improved animal performance in the novel object recognition test in comparison with animals maintained on reduced Mg intake and supplemented with various Mg compounds. These observations indicate that brain [Mg2+] is more sensitive to a short-term and moderate reduction in Mg dietary intake than previously thought and emphasizes the importance of dietary Mg in replenishing brain Mg2+ reserves. [ABSTRACT FROM AUTHOR]

A rACE to beat Alzheimer's disease: Alzheimer's disease (AD) has a strong genetic component and several genes have been associated with disease susceptibility, including the angiotensin-converting enzyme (ACE). Here, Cuddy et al. investigated the mechanistic link between ACE and AD using whole-genome sequencing databases and mouse models. The authors identified rare ACE variants associated with AD. They generated mice bearing a disease-associated mutation and showed increased neuronal ACE1 protein, neurodegeneration, and neuroinflammation with female animals developing a more severe phenotype. The variant accelerated disease development in a mouse model of AD and ACE inhibition rescued neuronal loss. The results suggest that ACE inhibitors might be effective in a subgroup of patients with AD. Recent genome-wide association studies identified the angiotensin-converting enzyme gene (ACE) as an Alzheimer's disease (AD) risk locus. However, the pathogenic mechanism by which ACE causes AD is unknown. Using whole-genome sequencing, we identified rare ACE coding variants in AD families and investigated one, ACE1 R1279Q, in knockin (KI) mice. Similar to AD, ACE1 was increased in neurons, but not microglia or astrocytes, of KI brains, which became elevated further with age. Angiotensin II (angII) and angII receptor AT1R signaling were also increased in KI brains. Autosomal dominant neurodegeneration and neuroinflammation occurred with aging in KI hippocampus, which were absent in the cortex and cerebellum. Female KI mice exhibited greater hippocampal electroencephalograph disruption and memory impairment compared to males. ACE variant effects were more pronounced in female KI mice, suggesting a mechanism for higher AD risk in women. Hippocampal neurodegeneration was completely rescued by treatment with brain-penetrant drugs that inhibit ACE1 and AT1R. Although ACE variant-induced neurodegeneration did not depend on β-amyloid (Aβ) pathology, amyloidosis in 5XFAD mice crossed to KI mice accelerated neurodegeneration and neuroinflammation, whereas Aβ deposition was unchanged. KI mice had normal blood pressure and cerebrovascular functions. Our findings strongly suggest that increased ACE1/angII signaling causes aging-dependent, Aβ-accelerated selective hippocampal neuron vulnerability and female susceptibility, hallmarks of AD that have hitherto been enigmatic. We conclude that repurposed brain-penetrant ACE inhibitors and AT1R blockers may protect against AD. [ABSTRACT FROM AUTHOR]

Phenotyping mouse model systems of human disease has proven to be a difficult task, with frequent poor inter‐ and intra‐laboratory replicability, particularly in behavioral domains such as social and cognitive function. However, establishing robust animal model systems with strong construct validity is of fundamental importance as they are central tools for understanding disease pathophysiology and developing therapeutics. To complete our studies of mouse model systems relevant to autism spectrum disorder (ASD), we present a replication of the main findings from our two published studies of five genetic mouse model systems of ASD. To assess the intra‐laboratory robustness of previous results, we chose the two model systems that showed the greatest phenotypic differences, the Shank3/F and Cntnap2, and repeated assessments of general health, activity and social behavior. We additionally explored all five model systems in the same framework, comparing all results obtained in this three‐yearlong effort using informatics techniques to assess commonalities and differences. Our results showed high intra‐laboratory replicability of results, even for those with effect sizes that were not particularly large, suggesting that discrepancies in the literature may be dependent on subtle but pivotal differences in testing conditions, housing enrichment, or background strains and less so on the variability of the behavioral phenotypes. The overall informatics analysis suggests that in our behavioral assays we can separate the set of tested mouse model system into two main classes that in some aspects lie on opposite ends of the behavioral spectrum, supporting the view that autism is not a unitary concept. [ABSTRACT FROM AUTHOR]

Early life nutrition plays an important role in brain development. Emerging research in rodents, piglets and humans suggest that prebiotics, milk fat globule membrane and lactoferrin may each play unique roles in brain development and cognitive functions. However, knowledge of their combined impact is lacking. We show here that providing weanling rats with a diet containing milk fat globule membrane, lactoferrin and a polydextrose/galactooligosaccharide prebiotic blend led to a significant increase in total dendritic spine density in hippocampal dentate gyrus neurons. Region-specific alterations in dendritic spine density and morphology could provide a mechanistic basis underlying broader cognitive benefits, but further research is required to demonstrate functional consequences of these observations. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder comprises several neurodevelopmental conditions presenting symptoms in social communication and restricted, repetitive behaviors. A major roadblock for drug development for autism is the lack of robust behavioral signatures predictive of clinical efficacy. To address this issue, we further characterized, in a uniform and rigorous way, mouse models of autism that are of interest because of their construct validity and wide availability to the scientific community. We implemented a broad behavioral battery that included but was not restricted to core autism domains, with the goal of identifying robust, reliable phenotypes amenable for further testing. Here we describe comprehensive findings from two known mouse models of autism, obtained at different developmental stages, using a systematic behavioral test battery combining standard tests as well as novel, quantitative, computer-vision based systems. The first mouse model recapitulates a deletion in human chromosome 16p11.2, found in 1% of individuals with autism. The second mouse model harbors homozygous null mutations in Cntnap2, associated with autism and Pitt-Hopkins-like syndrome. Consistent with previous results, 16p11.2 heterozygous null mice, also known as Del(7Slx1b-Sept1)4Aam weighed less than wild type littermates displayed hyperactivity and no social deficits. Cntnap2 homozygous null mice were also hyperactive, froze less during testing, showed a mild gait phenotype and deficits in the three-chamber social preference test, although less robust than previously published. In the open field test with exposure to urine of an estrous female, however, the Cntnap2 null mice showed reduced vocalizations. In addition, Cntnap2 null mice performed slightly better in a cognitive procedural learning test. Although finding and replicating robust behavioral phenotypes in animal models is a challenging task, such functional readouts remain important in the development of therapeutics and we anticipate both our positive and negative findings will be utilized as a resource for the broader scientific community. [ABSTRACT FROM AUTHOR]

Aims: To study the effects of a novel matrix metalloproteinase-2 (MMP-2) and MMP-9 inhibitor, AQU-118, on mechanical allodynia in the spinal nerve ligation (SNL) model of neuropathic pain and the chronic constriction injury of the infraorbital nerve (CCI-IoN) model of neuropathic orofacial pain. Methods: Five groups of SNL rats were given daily oral doses of AQU-118 (5, 10, 20 mg/kg), gabapentin (100 mg/kg), or vehicle (0.5% methylcellulose) and then paw withdrawal threshold was measured with von Frey filaments (VF). Three groups of CCI-IoN rats were given daily oral doses of either AQU-118 (40 mg/kg), gabapentin (100 mg/kg), or vehicle (0.5% methylcellulose) and then mechanical allodynia was measured with facial VF and non-reflex-based orofacial stimulation test (OFST) assay. Naive rats were also tested for the effect of AQU-118 (40 mg/kg) on basal sensitivity to mechanical stimulation/locomotive activity. Results: Mechanical allodynia in SNL rats was attenuated by gabapentin (100 mg/kg) and AQU-118 (in a dose-dependent manner). Mechanical allodynia in CCI-IoN rats was also attenuated (in an equipotent manner) by both AQU-118 (40 mg/ kg) and gabapentin (100 mg/kg) as measured by both facial VF and OFST assay. Upon cessation of either AQU-118 or gabapentin, VF-related responses in both models and OFST assay times reverted to levels observed in vehicle-treated rats. No statistically significant change was observed in locomotive activity/paw withdrawal threshold by AQU-118 (40 mg/kg) in naive rats. Conclusion: The results demonstrated that oral AQU-118 attenuates mechanical allodynia in both neuropathic pain models and with efficacies that mirror gabapentin at the 40 mg/kg dose used in the CCI-IoN model but without effect on basal sensitivity to mechanical stimulation/locomotive activity. These findings support a possible role for MMP-2/-9 in the etiology of neuropathic pain and also suggest that inhibition strategies represent a viable treatment option. [ABSTRACT FROM AUTHOR]

Noribogaine, a polypharmacological drug with activities at opioid receptors, ionotropic nicotinic receptors, and serotonin reuptake transporters, has been investigated for treatment of substance abuse-related disorders. Smoking cessation has major benefits for both individuals and society, therefore the aim of this study was to evaluate the potential of noribogaine for use as a treatment for nicotine dependence. Adult male Sprague-Dawley rats were trained to self-administer nicotine intravenous. After initial food pellet training, followed by 26 sessions of nicotine self-administration training, the rats were administered noribogaine (12.5, 25 or 50 mg/kg orally), noribogaine vehicle, varenicline or saline using a within-subject design with a Latin square test schedule. Noribogaine dose-dependently decreased nicotine self-administration by up to 64% of saline-treated rats’ levels and was equi-effective to 1.7 mg/kg intraperitoneal varenicline. Noribogaine was less efficient at reducing food pellets self-administration than at nicotine self-administration, inhibiting the nondrug reinforcing effects of palatable pellets by 23% at the highest dose. These results suggest that noribogaine dose-dependently attenuates drug-taking behavior for nicotine, attenuates the reinforcing effects of nicotine and is comparable to varenicline power in that regard. The findings from the present study hold promise for a new therapy to aid smoking cessation. [ABSTRACT FROM PUBLISHER]

Preclinical and clinical studies demonstrated that the inhibition of cholinergic supersensitivity through nicotinic antagonists and partial agonists can be used successfully to treat depressed patients, especially those who are poor responders to selective serotonin reuptake inhibitors (SSRIs). In our effort to develop novel antidepressant drugs, LF-3-88 was identified as a potent nicotinic acetylcholine receptor ( nAChR) partial agonist with subnanomolar to nanomolar affinities for β2-containing nAChRs ( α2 β2, α3 β2, α4 β2, and α4 β2*) and superior selectivity away from α3 β4 − ( Ki > 104 nmol/L) and α7- nAChRs ( Ki > 104 nmol/L) as well as 51 other central nervous system (CNS)-related neurotransmitter receptors and transporters. Functional activities at different nAChR subtypes were characterized utilizing 86Rb+ ion efflux assays, two-electrode voltage-clamp (TEVC) recording in oocytes, and whole-cell current recording measurements. In mouse models, administration of LF-3-88 resulted in antidepressive-like behavioral signatures 15 min post injection in the SmartCube® test (5 and 10 mg/kg, i.p.; about 45-min session), decreased immobility in the forced swim test (1-3 mg/kg, i.p.; 1-10 mg/kg, p.o.; 30 min pretreatment, 6-min trial), and decreased latency to approach food in the novelty-suppressed feeding test after 29 days chronic administration once daily (5 mg/kg but not 10 mg/kg, p.o.; 15-min trial). In addition, LF-3-88 exhibited a favorable profile in pharmacokinetic/ADME-Tox (absorption, distribution, metabolism, excretion, and toxicity) assays. This compound was also shown to cause no mortality in wild-type Balb/CJ mice when tested at 300 mg/kg. These results further support the potential of potent and selective nicotinic partial agonists for use in the treatment of depression. [ABSTRACT FROM AUTHOR]

Suberoylanilide hydroxamic acid (SAHA) is an inhibitor of histone deacetylases (HDACs) used for the treatment of cutaneous T cell lymphoma (CTCL) and under consideration for other indications. In vivo studies suggest reducing HDAC function can enhance synaptic function and memory, raising the possibility that SAHA treatment could have neurological benefits. We first examined the impacts of SAHA on synaptic function in vitro using rat organotypic hippocampal brain slices. Following several days of SAHA treatment, basal excitatory but not inhibitory synaptic function was enhanced. Presynaptic release probability and intrinsic neuronal excitability were unaffected suggesting SAHA treatment selectively enhanced postsynaptic excitatory function. In addition, long-term potentiation (LTP) of excitatory synapses was augmented, while long-term depression (LTD) was impaired in SAHA treated slices. Despite the in vitro synaptic enhancements, in vivo SAHA treatment did not rescue memory deficits in the Tg2576 mouse model of Alzheimer’s disease (AD). Along with the lack of behavioral impact, pharmacokinetic analysis indicated poor brain availability of SAHA. Broader assessment of in vivo SAHA treatment using high-content phenotypic characterization of C57Bl6 mice failed to demonstrate significant behavioral effects of up to 150 mg/kg SAHA following either acute or chronic injections. Potentially explaining the low brain exposure and lack of behavioral impacts, SAHA was found to be a substrate of the blood brain barrier (BBB) efflux transporters Pgp and Bcrp1. Thus while our in vitro data show that HDAC inhibition can enhance excitatory synaptic strength and potentiation, our in vivo data suggests limited brain availability may contribute to the lack of behavioral impact of SAHA following peripheral delivery. These results do not predict CNS effects of SAHA during clinical use and also emphasize the importance of analyzing brain drug levels when interpreting preclinical behavioral pharmacology. [ABSTRACT FROM AUTHOR]

Impulsivity is a heterogeneous construct according to clinical and preclinical behavioural measures and there is some preliminary evidence indicating distinct neurobiological substrates underlying the sub-components of impulsivity. Two preclinical assays, the five-choice serial reaction time task (5-CSRTT) and the delayed discounting task (DDT), are hypothesized to provide measures of impulsive action (premature responding) and impulsive choice (percent choice for delayed reward), respectively. In the present studies, we show that the norepinephrine reuptake inhibitor atomoxetine attenuated premature responding in the 5-CSRTT, but was ineffective in the DDT. The mixed dopamine/norepinephrine reuptake inhibitor methylphenidate exhibited an opposite profile of effects. In addition, blockade of 5-HT2A/C receptors via ketanserin decreased premature responding but had no effects on percent choice for delayed reward; blockade of 5-HT2C receptors via SB 242084 had opposite effects. Follow-up studies provided some limited evidence of additive effects of 5-HT2A/C receptor blockade on the effects of atomoxetine on impulsive action. These studies demonstrate dissociable profiles of stimulant vs. non-stimulant attention deficit hyperactivity disorder medications and 5-HT subtype-selective ligands, in the 5-CSRTT and DDT assays. Thus, the present findings support the sub-categorization of impulsivity and suggest that 5-HT receptor subtype-selective antagonists may provide therapeutic targets for disorders characterized by different forms of impulsivity. [ABSTRACT FROM PUBLISHER]

Insulin-like growth factor I (IGF-I) has been successfully tested in the SOD1-G93A mouse model of familial amyotrophic lateral sclerosis (ALS) and proposed for clinical treatment. However, beneficial effects required gene therapy or intrathecal application. Circumventing the dosing issues we recently found that polyethylene glycol (PEG) modified IGF-I (PEG-IGF-I) modulated neuromuscular function after systemic application, and protected against disease progression in a motor neuron disease model. Here we investigated its effects in two SOD1-G93A mouse lines, the G1L with a milder and the G1H with a more severe phenotype. Results showed that in G1L mice, PEG-IGF-I treatment significantly improved muscle force, motor coordination and animal survival. In contrast, treatment of G1H mice with PEG-IGF-I or IGF-I even at high doses did not beneficially affect survival or functional outcomes despite increased signalling in brain and spinal cord by both agents. In conclusion, the data point towards further investigation of the therapeutic potential of PEG-IGF-I in ALS patients with less severe clinical phenotypes. [ABSTRACT FROM AUTHOR]

There is a need for antidepressants with novel mechanisms of action. One approach has been to develop compounds that inhibit reuptake of all three monoamines in the central nervous system, for example DOV216,303. Differential reinforcement of low-rate (72-s) responding is a behavioral test that is predictive of antidepressant-like properties. The effects of antidepressant compounds belonging to multiple classes, the anxiolytic diazepam and the antipsychotic haloperidol, were assessed in the DRL-72s task. Subsequently, the antidepressant-like properties of acute DOV216,303 were assessed. The selective serotonin reuptake inhibitor fluvoxamine, the preferential norepinephrine reuptake inhibitor desipramine and the tricyclic antidepressant imipramine exhibited antidepressant-like properties in the DRL-72s task. The atypical antidepressant bupropion, which inhibits dopamine and norepinephrine reuptake, and the selective dopamine transporter inhibitor GBR12909, changed reinforcement and response rates and inter-response time distribution in an opposite direction compared with the antidepressant compounds tested. The antipsychotic haloperidol exhibited antidepressant-like properties by increasing reinforcement rate, but failed to alter inter-response time distribution. Diazepam did not change reinforcement or response rates or inter-response time distribution. The triple reuptake inhibitor DOV216,303 significantly enhanced reinforcement rate at one intermediate dose, but exhibited similar effects as bupropion and GBR12909 on inter-response time distribution. The studies identified limited antidepressant-like properties of the triple reuptake inhibitor DOV216,303, likely due to dopamine transporter inhibition counteracting the effects of norepinephrine and serotonin transporter inhibition. [ABSTRACT FROM PUBLISHER]

Abstract: Rationale: Both the GABAB receptor positive modulator GS39783 and the GABAB receptor antagonist CGP46381 exhibit anxiolytic-like properties in animal models. In the present studies, the effects of GS39783 and CGP46381 in the modified Geller–Seifter task were assessed. First, the predictive validity of the task was confirmed by assessing the effects of multiple anxiolytic and non-anxiolytic compounds on punished and unpunished responding. Methods: Rats were trained in the modified Geller–Seifter task. After successful acquisition of the task, chlordiazepoxide, diazepam, MPEP, haloperidol, GS39783, 8-OH-DPAT, alprazolam and CGP46381 were tested consecutively. For each test compound, doses were administered in a randomized, counter-balanced, within-subjects design. Drug tests were performed only when rats exhibited baseline performance (the punished and time-out response rates were less than 10% of the unpunished response rate). Results: Chlordiazepoxide, diazepam, alprazolam and MPEP released punished responding with variable effects on unpunished responding. Haloperidol had a small but significant effect on punished responding at an intermediate dose, and decreased unpunished responding at the highest dose tested. In contrast, administration of the GABAB receptor positive modulator GS398783 or the GABAB receptor antagonist CGP46381 at doses up to 30mg/kg had no effects on either punished or unpunished responding. The 5-HT1A agonist 8-OH-DPAT did not release punished responding, but significantly decreased unpunished responding at the highest dose tested. Summary: The modified Geller–Seifter task generally exhibits good predictive validity for anxiolytic-like compounds. Neither GABAB receptor positive allosteric modulation nor blockade exhibited anxiolytic-like properties in the modified Geller–Seifter task. The 5-HT1A partial agonist buspirone was similarly ineffective. [Copyright &y& Elsevier]

The locomotor-stimulant effects of cocaine, mediated through inhibition of the dopamine transporter (DAT'), can be influenced by environmental factors. Previously, we found that following a short exposure to the testing environment, cocaine induces greater locomotor activation in inbred long-sleep (ILS) mice, compared to inbred short-sleep (155) mice. In the present study, all animals received prolonged habituation to the testing chambers prior to cocaine injection, and the results were compared with those from our previous study. When mice were tested with saline on day 1 and with either saline or cocaine (10-20 mg/kg) on day 2, we observed significant locomotor stimulation in ILS, but not ISS, mice at all tested doses of cocaine. Thus, prolonged habituation does not alter the differential responsiveness of these two strains of mice to cocaine. We found no strain differences in striatal cocaine levels. However, [3H]WIN 35,428 binding studies showed a lower number of striatal DATs in ILS, compared to ISS, mice. In vivo analysis of striatal DAT activity revealed not only that ILS mice cleared exogenously applied DA more slowly than ISS mice, but also that cocaine (10 mg/kg) decreased DA clearance selectively in ILS mice. Thus, functional differences in striatal DATs between ILS and ISS mice likely contribute to the differential behavioral activation of cocaine in these two mouse strains. [ABSTRACT FROM AUTHOR]

Background: The actions of ethanol in the brain involve multiple neuroreceptor systems, including glutamatergic N-methyl-D-aspartate receptor (NMDAR) channels. In a novel environment, both ethanol and the noncompetitive NMDAR antagonist MK-801 stimulate locomotor activity to a lesser extent in inbred long-sleep (ILS) mice compared with inbred short-sleep (ISS) mice. The behaviorally activating effects of noncompetitive NMDAR antagonists are thought to involve increased monoamine neurotransmission. Thus, in this study, we sought to determine whether: (1) habituation to the behavioral environment alters the differential locomotor-stimulant effects of noncompetitive NMDAR antagonists in ILS and ISS mice and (2) the differential behavioral sensitivity of ILS and ISS mice to noncompetitive NMDAR antagonists is mediated through direct inhibition of the dopamine transporter (DAT). Methods: Open field locomotor activity was measured following acute systemic injection of saline or drug. [3H]DA uptake parameters were determined in striatal synaptosomes prepared from drug-naïve mice. Results: Habituation to the testing environment abolished the strain differences in saline-induced locomotor activity. However, ethanol- as well as MK-801-treated ILS mice still exhibited reduced locomotor activity compared with ISS mice, suggesting that a drug-environment interaction is not the primary explanation for the strain differences. The noncompetitive NMDAR antagonists phencyclidine and ketamine also induced significantly lower locomotor activity in ILS than in ISS mice. In contrast, the DAT inhibitors cocaine and GBR 12909 and the DA releaser amphetamine induced greater locomotor activity in ILS than in ISS mice, a strain difference opposite that of the noncompetitive NMDAR antagonists. Furthermore, the differential behavioral effect found with DAT inhibitors was not mediated by differences in the affinity nor number of striatal DATs between ILS and ISS mice. Conclusions: Our results support the conclusion that the differential locomotor-stimulant effects of ethanol and noncompetitive NMDAR antagonists in ILS and ISS mice are not mediated through direct inhibition of DAT. [ABSTRACT FROM AUTHOR]

Background: Short-sleep (SS) mice exhibit higher locomotor activity than do long-sleep (LS) mice when injected with low doses of ethanol or the noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist MK-801 (dizocilpine). SS mice also have higher densities of brain NMDARs. However, two strains of LS X SS recombinant inbred (RI) mice also show differential activation to ethanol and MK-801, but have similar numbers of NMDARs. Here we used inbred LS (ILS) and SS (ISS) mice to investigate further the relationship between NMDARs and sensitivity to the stimulant effects of low doses of ethanol. Methods: Open field activity and spontaneous alternations were measured after saline or drug injection. [3H]MK-801 binding parameters were determined in hippocampus, cortex, striatum, and nucleus accumbens. Extracellular field excitatory postsynaptic potentials (fEPSPs) were recorded in the CA1 region of hippocampal slices. Results: Systemic injection of either ethanol or MK-801 increased locomotor activity to a greater extent in ISS mice than in ILS mice. The competitive NMDAR antagonist 2-carboxypiperazin-4-yl-propyl-1-1phosphonic acid (±CPP) depressed activity of ILS, but not ISS, mice. No strain differences were observed in spontaneous alternations or in the number or affinity of NMDARs in the brain regions examined. Likewise, the magnitudes of hippocampal NMDAR-mediated fEPSPs were similar in ILS and ISS mice and were inhibited to the same extent by a competitive NMDAR antagonist. However, both ethanol and the NMDAR NR2B receptor antagonist ifenprodil inhibited the late component of hippocampal NMDAR fEPSPs to a greater extent in ISS, than in ILS, mice. Conclusions: Differential ethanol- and MK-801-induced behavioral activation in ILS and ISS mice was not associated with differences in NMDAR number. Nonetheless, pharmacological differences in hippocampal NMDAR responsiveness suggest that ISS mice express NMDARs that have a greater sensitivity to noncompetitive, but not competitive, NMDAR antagonists. These differences, which may reflect differences in NMDAR subunit composition, could underlie the differential responsiveness to low doses of ethanol in ILS and ISS mice. [ABSTRACT FROM AUTHOR]

Background Law doses of the N-methyl-D-aspartate receptor (NMDAR) antagonist MK-801 (dizocilpine) or ethanol increase locomotor activity to a lesser extent in long-sleep (LS), than in short-sleep (SS), mice. LS mice also have fewer brain (3H]MK-801 binding sites than SS mice. In this study, LSXSS recombinant inbred (RI) mice were used to investigate whether different NMDAR densities contribute to differential MK-801 activation and whether common genes are involved in initial sensitivity to MK-801- and ethanol-induced activation. Methods Locomotor activity was measured for 90 min after saline or MK-801 injection. Quantitative autoradiographic analysis of [3H]MK-801 binding was used to measure densities of NMDARs in seven brain regions. The ethanol (1-2 gkg) activation scores from Erwin and colleagues (1997) were used for correlational analysis, as was their method for quantitative trait loci (QTL) analysis. Results Both saline and MK-801 (0.3 mgkg, given intraperitoneally) induced a continuum of locomotor responses across the LSXSS RI strains. There was a 4-fold range of MK-801 difference scores (MK-801 score-saline baseline), with the RI 9 and RI 4 strains representing low and high responders, respectively. Dose-response experiments with these two strains confirmed that 0.3 mgkg MK-801 produced significant activation, similar to previous results with LS and SS mice. However, unlike previous LS/SS results, lower densities of NMDARs were not observed in the RI 9 than in the RI 4 mouse brains. No significant genetic correlations were observed between MK-801-induced and ethanol-induced responses in the LSXSS RI mice. Two provisional MK-801 activation QTLs were identified ( p < 0.01) on chromosomes 11 and 19, neither in common with those mapped for ethanol activation. Conclusions Different densities of brain NMDARs are unlikely to account for the differential activation of LSXSS RI mice by MK-801. Additionally, in the RI mice either separate sets of genes regulate low dose MK-801- and ethanol-induced locomotor responses or the overlapping subset of genes controlling these two behaviors is small (≤ 10%). [ABSTRACT FROM AUTHOR]

There is an unmet medical need for the development of non-addicting pain therapeutics with enhanced efficacy and tolerability. The current study examined the effects of AQU-118, an orally active inhibitor of metalloproteinase-2 (MMP-2) and MMP-9, in the spinal nerve ligation (SNL) rat model of neuropathic pain. Mechanical allodynia and the levels of various biomarkers were examined within the dorsal root ganglion (DRG) before and after oral dosing with AQU-118. The rats that received the SNL surgery exhibited significant mechanical allodynia as compared to sham controls. Animals received either vehicle, positive control (gabapentin), or AQU-118. After SNL surgery, the dorsal root ganglion (DRG) of those rats dosed with vehicle had elevated messenger RNA (mRNA) expression levels for MMP-2, IL1-β & IL-6 and elevated protein levels for caspase-3 while exhibiting decreased protein levels for myelin basic protein (MBP) & active IL-β as compared to sham controls. Rats orally dosed with AQU-118 exhibited significantly reduced mechanical allodynia and decreased levels of caspase-3 in the DRG as compared to vehicle controls. Results demonstrate that oral dosing with the dual active, MMP-2/-9 inhibitor, AQU-118, attenuated mechanical allodynia while at the same time significantly reduced the levels of caspase-3 in the DRG. [ABSTRACT FROM AUTHOR]