158 results on '"Stephan Hjorth"'
Search Results
52. ChemInform Abstract: trans-2-Aryl-N,N-dipropylcyclopropylamines: Synthesis and Interactions with 5-HT1A Receptors
- Author
-
Jerk Vallgarda, Stephan Hjorth, B. E. Svensson, Uli Hacksell, L.-E. Arvidsson, and Ulf Appelberg
- Subjects
chemistry.chemical_compound ,chemistry ,Stereochemistry ,Aryl ,General Medicine ,Receptor ,Thiophene derivatives - Published
- 2010
53. ChemInform Abstract: 10-Substituted 11-Oxygenated (R)-Aporphines: Synthesis, Pharmacology, and Modeling of 5-HT1A Receptor Interactions
- Author
-
Stephan Hjorth, Johanna M. Jansen, Anette M. Johansson, Lena Unelius, Martin H. Hedberg, and Gunnar Nordvall
- Subjects
Steric effects ,Agonist ,Chemistry ,Stereochemistry ,medicine.drug_class ,General Medicine ,Aporphines ,Affinities ,Dopamine ,medicine ,5-HT1A receptor ,Serotonin ,Receptor ,medicine.drug - Abstract
Derivatives of the selective serotonin 5-HT1A receptor agonist (R)-11-hydroxy-10-methylaporphine (2) having various substituents in the C10-position or at the nitrogen have been synthesized from natural morphine or 6-O-acetylcodeine, respectively. The C10-substituents were introduced using efficient Stille or Suzuki cross-coupling reactions. The compounds were evaluated for their affinities to 5-HT1A and dopamine (DA) D1 and D2A receptors in vitro. All compounds tested displayed low (micromolar) affinities to D1 and D2A receptors. In addition, changes in steric bulk and/or electronic properties of the C10-substituent as compared to a C10-methyl group, as well as substitution of the N-methyl group for a hydrogen or a larger N-alkyl group, produced a marked decrease in the affinities to 5-HT1A receptors. Selected compounds that displayed moderate to high affinities to 5-HT1A receptors were evaluated for their ability to stimulate 5-HT1A receptors in vivo. The evaluated compounds behaved as agonists at 5-HT1...
- Published
- 2010
54. ChemInform Abstract: 11-Substituted (R)-Aporphines: Synthesis, Pharmacology, and Modeling of D2A and 5-HT1A Receptor Interactions
- Author
-
Tero Linnanen, Johanna M. Jansen, Anette M. Johansson, Lena Unelius, Martin H. Hedberg, Gunnar Nordvall, and Stephan Hjorth
- Subjects
Steric effects ,Sulfonyl ,chemistry.chemical_classification ,chemistry.chemical_compound ,Trifluoromethyl ,chemistry ,Stereochemistry ,Substituent ,General Medicine ,Serotonin ,Aporphine ,Receptor ,Trifluoromethanesulfonate - Abstract
A series of C11-substituted (R)-aporphines and C11-oxygenated (R)-noraporphines has been synthesized and evaluated for central serotonergic and dopaminergic effects in vitro and in vivo. The various C11-substituents were introduced using efficient nickel- and palladium-catalyzed reactions of the corresponding triflate (R)-11-[[(trifluoromethyl)sulfonyl]oxy]aporphine (6). Several compounds display high affinity to serotonin 5-HT1A receptors in spite of major differences in steric bulk and electronic properties of the various C11-substituents. A change of the N-methyl group of the nonselective 3 to H [23, (R)-11-hydroxynoraporphine] or propyl [2, (R)-11-hydroxy-N-propylnoraporphine] increases the selectivity for 5-HT1A receptors (100-fold) and dopamine D2A receptors (3-fold), respectively. Compounds 3 and 23 have similar affinities to 5-HT1A receptors, whereas the propyl substituent of 2 not only enhances the selectivity for D2A receptors but also increases the D2A affinity. Modeling of ligand−receptor bind...
- Published
- 2010
55. Binding properties of antagonists to cannabinoid receptors in intact cells
- Author
-
Marie, Wennerberg, Leifeng, Cheng, Stephan, Hjorth, John C, Clapham, Anudharan, Balendran, and Georges, Vauquelin
- Subjects
HEK293 Cells ,Time Factors ,Piperidines ,Receptor, Cannabinoid, CB1 ,Pyridines ,Humans ,Pyrazoles ,Serum Albumin, Bovine ,Sulfones ,Rimonabant ,Ligands ,Amides ,Protein Binding - Abstract
The implication of the cannabinoid receptor 1 (CB(1) receptor) in several pathophysiological states has sparked the development of selective antagonists. Here we compare binding of the antagonists [(3) H]-AZ12491187, [(3) H]-taranabant and [(3) H]-rimonabant to intact human embryonic kidney cells stably expressing recombinant human CB(1) receptors (CB1r cells). Unlabelled ligands decreased the total binding of the three radioligands with closely the same order of potency: i.e. AZ12288553∼AZ12491187∼taranabantrimonabant. Nondisplaceable (i.e. nonspecific) binding to the CB1r cells was the same as total binding to the wells containing untransfected cells and it was more pronounced for [(3) H]-AZ12491187 and [(3) H]-rimonabant than for [(3) H]-taranabant. [(3) H]-Rimonabant and (to a lesser extent) [(3) H]-AZ12491187 were also prone to bind nonspecifically to the walls of the wells. Compared to the other radioligands, [(3) H]-rimonabant displayed lower potency for the CB(1) receptors in saturation binding studies and faster association and dissociation in kinetic experiments. When dissociated, the three radioligands also showed prominent rebinding to the cells in medium only. This could be relieved by the presence of excess of unlabelled ligand and of bovine serum albumin (BSA) but a combination thereof was most efficient. The long 'residence time' of AZ12491187 at the CB(1) receptor (because of slow dissociation and prominent rebinding) and its pronounced incorporation into the membranes of the cells could contribute to long-lasting in vivo CB(1) receptor blockade.
- Published
- 2010
56. (−)-penbutolol as a blocker of central 5-HT1A receptor-mediated responses
- Author
-
Stephan Hjorth
- Subjects
Male ,Agonist ,Serotonin ,medicine.medical_specialty ,Reserpine ,medicine.drug_class ,In Vitro Techniques ,Pharmacology ,Body Temperature ,5-Hydroxytryptophan ,Rats, Sprague-Dawley ,Penbutolol ,In vivo ,Postsynaptic potential ,Internal medicine ,medicine ,Animals ,Receptor ,5-HT receptor ,Brain Chemistry ,8-Hydroxy-2-(di-n-propylamino)tetralin ,Behavior, Animal ,Chemistry ,musculoskeletal, neural, and ocular physiology ,Antagonist ,Stereoisomerism ,Rats ,Endocrinology ,nervous system ,5-HT1A receptor ,Serotonin Antagonists ,medicine.drug - Abstract
Brain 5-HT1A and 5-HT1B receptors are important targets for drug-induced modulation of 5-HT function in vivo. However, very few compounds are available that are effective antagonists at 5-HT1 receptors, thus hampering the progress of fundamental as well as clinical research in this area. The present study assessed the usefulness of the beta-adrenolytic agent (-)-penbutolol (and its (+)-counterpart) as a 5-HT1A receptor-blocking agent. The compound was found to counteract, in a stereospecific fashion, not only the behavioural and hypothermic but also the in vivo 5-HT synthesis/turnover-reducing effects of the specific 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). These findings indicate that (-)-penbutolol is an antagonist at both postsynaptic receptors and somatodendritic autoreceptors of the 5-HT1A subtype. Thus, (-)-penbutolol represents a useful addition to the array of pharmacological tools available for the study of central 5-HT1 receptor-mediated functions.
- Published
- 1992
57. Dopamine fiber growth induction by implantation of synthetic dopamine-containing microspheres in rats with experimental hemi-parkinsonism
- Author
-
A. McRae, Lynn Dillon, Annica Dahlström, Stephan Hjorth, David W. Mason, and Thomas R. Tice
- Subjects
Male ,medicine.medical_specialty ,Tyrosine 3-Monooxygenase ,Dopamine ,Drug Compounding ,medicine.medical_treatment ,Nerve Tissue Proteins ,Striatum ,Receptors, Dopamine ,Postsynaptic potential ,Internal medicine ,medicine ,Animals ,Parkinson Disease, Secondary ,Oxidopamine ,Receptor ,Medial forebrain bundle ,Molecular Biology ,Drug Implants ,Tyrosine hydroxylase ,Chemistry ,General Neuroscience ,Growth factor ,Corpus Striatum ,Nerve Regeneration ,Rats ,Up-Regulation ,Apomorphine ,Endocrinology ,Neurology (clinical) ,medicine.drug - Abstract
Injectable local drug delivery formulations—so-called microspheres —have recently been developed, in which drugs are microencapsulated within biocompatible and biodegradable copolymer excipients like poly[DL-lactide-co-glycolide]. In view of its potential therapeutical usefulness, we have studied the microsphere methodology as a means to substitute for experimentally induced subnormal levels of endogenous dopamine (DA). Administration of 6-hydroxydopamine (6-OH-DA) unilaterally in the medial forebrain bundle of rats results in an up-regulation of postsynaptic receptors in the denervated striatum, functionally manifested as contralateral rotational behavior after apomorphine. DA microspheres were implanted in the denervated striatum. The majority of the rats displayed an attenuation of the contralateral rotational behavior induced by apomorphine up to 8 wk postimplantation. Immunocytochemical observations unexpectedly demonstrated growth of DA and tyrosine hydroxylase immunoreactive fibers in the denervated striatum. Interestingly, there was an apparent correlation between functional recovery and the degree of growth of DA fibers. The present results suggest that implantation of DA microspheres may promote DA fiber growth and extended recovery of surviving DA neurons, and, therefore, could be of therapeutic usefulness in Parkinson’s disease.
- Published
- 1992
58. Novel thioamide derivatives as neutral CB1 receptor antagonists
- Author
-
Erik Ryberg, Leifeng Cheng, Henrik Nordberg, Jonas Boström, Roine I. Olsson, Peter J. Greasley, Joakim Tholander, and Stephan Hjorth
- Subjects
Stereochemistry ,medicine.drug_class ,Clinical Biochemistry ,Pharmaceutical Science ,Mice, Obese ,Carboxamide ,Biochemistry ,Chemical synthesis ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,Receptor, Cannabinoid, CB1 ,Drug Discovery ,medicine ,Animals ,Obesity ,Receptor ,Molecular Biology ,Thioamide ,chemistry.chemical_classification ,Organic Chemistry ,Antagonist ,Biological activity ,Thioamides ,Disease Models, Animal ,chemistry ,Pyrazines ,Molecular Medicine ,Lawesson's reagent ,Anti-Obesity Agents ,Linker - Abstract
A novel class of cannabinoid-1 (CB1) receptor antagonists for the treatment of obesity is presented. The carboxamide linker in a set of 5,6-diaryl-pyrazine-2-amide derivatives was transformed into the corresponding thioamide, by using a one-pot synthesis. The structural series of thioamides not only showed retained CB1 potency (below 10 nM), but also showed improved solubility. In addition, the neutral antagonist 2c significantly reduced body weight in cafeteria diet obese mice.
- Published
- 2009
59. Single-dose 8-OH-DPAT pretreatment does not Induce tachyphylaxis to the 5-HT release-reducing effect of 5-HT1A autoreceptor agonists
- Author
-
Stephan Hjorth
- Subjects
Male ,Agonist ,Serotonin ,medicine.medical_specialty ,Microdialysis ,Tetrahydronaphthalenes ,medicine.drug_class ,Population ,Tachyphylaxis ,Pharmacology ,Hippocampus ,Piperazines ,Feedback ,chemistry.chemical_compound ,Internal medicine ,polycyclic compounds ,medicine ,Animals ,heterocyclic compounds ,education ,8-Hydroxy-2-(di-n-propylamino)tetralin ,education.field_of_study ,Binding Sites ,8-OH-DPAT ,musculoskeletal, neural, and ocular physiology ,Ipsapirone ,Rats, Inbred Strains ,Rats ,Pyrimidines ,Endocrinology ,nervous system ,chemistry ,Receptors, Serotonin ,Autoreceptor ,medicine.drug ,Serotonin Agonist - Abstract
It has recently been suggested that central 5-HT1A autoreceptors are already desensitised after single-dose 5-HT1A agonist treatment. In turn, this would lead to an attenuated feedback suppression of transmitter release from 5-HT neurones, and thus to enhanced 5-HT synaptic transmission. In the present study in vivo brain microdialysis techniques were used in an attempt to test this hypothesis. The results show that single-dose pretreatment with the reference 5-HT1A receptor agonist 8-hydroxy-2-(din-propylamino)tetralin, 8-OH-DPAT, (i) did not significantly alter the baseline output of 5-HT in the rat ventral hippocampus 24 h later, and (ii) did not alter the release-reducing response to 5-HT1A agonist (8-OH-DPAT, ipsapirone or BMY 7378) challenge under the same conditions. These observations indicate that the functional responsiveness of the 5-HT release-controlling 5-HT1A autoreceptors is maintained after bolus 8-OH-DPAT pretreatment. When related to the acute 8-OH-DPAT-induced reduction in raphe 5-HT1A radioligand binding density recently reported by others, the present results are consistent with a large functional overcapacity of this 5-HT1A receptor population. The mechanism by which 5-HT1A receptor-mediated hypothermia and hyperphagia are rapidly attenuated by a previous large single dose of a 5-HT1A receptor agonist remains to be explained.
- Published
- 1991
60. Microencapsulated Dopamine (DA)-Induced Restitution of Function in 6-OHDA-Denervated Rat Striatumin vivo: Comparison Between Two Microsphere Excipients
- Author
-
Thomas R. Tice, Lynn Dillon, David W. Mason, Stephan Hjorth, and A. McRae
- Subjects
Male ,Apomorphine ,Dopamine ,Drug Compounding ,Central nervous system ,Excipient ,Motor Activity ,Pharmacology ,Article ,Excipients ,chemistry.chemical_compound ,In vivo ,medicine ,Animals ,Oxidopamine ,Polyglactin 910 ,Drug Implants ,Lactide ,Rats, Inbred Strains ,Denervation ,Corpus Striatum ,Microspheres ,Rats ,medicine.anatomical_structure ,Neurology ,chemistry ,Drug delivery ,Neurology (clinical) ,medicine.drug - Abstract
Biodegradable controlled-release microsphere systems made with the biocompatible biodegradable polyester excipient poly [DL lactide-co-glycolide] constitute an exciting new technology for drug delivery to the central nervous system (CNS). The present study describes functional observations indicating that implantation of dopamine (DA) microspheres encapsulated within two different polymer excipients into denervated- striatal tissue assures a prolonged release of the transmitterin vivo. Moreover, in this regard, the results show that there were clear cut temporal differences in the effect of the two DA microsphere formulations compared in this study, probably reflecting variations in the actual composition (i.e., lactide to glycolide ratio) of the two copolymer excipients examined. This technology has considerable potential for basic research with possible clinical application.
- Published
- 1991
61. Effects of MDL 73005EF on central pre- and postsynaptic 5-HT1A receptor function in the rat in vivo
- Author
-
Stephan Hjorth, Philip J. Cowen, and Sarah E. Gartside
- Subjects
Central Nervous System ,Male ,Agonist ,Serotonin ,endocrine system ,medicine.medical_specialty ,Tetrahydronaphthalenes ,Agonist-antagonist ,medicine.drug_class ,Pharmacology ,Biology ,Dioxins ,Hippocampus ,Adrenocorticotropic Hormone ,Postsynaptic potential ,Internal medicine ,Fenfluramine ,polycyclic compounds ,medicine ,Animals ,Spiro Compounds ,heterocyclic compounds ,Pindolol ,Receptor ,5-HT receptor ,8-Hydroxy-2-(di-n-propylamino)tetralin ,musculoskeletal, neural, and ocular physiology ,Rats, Inbred Strains ,Receptor antagonist ,Neurosecretory Systems ,Prolactin ,Rats ,Endocrinology ,nervous system ,Receptors, Serotonin ,Synapses ,5-HT1A receptor ,Serotonin Antagonists ,Dialysis ,medicine.drug - Abstract
The effects of MDL 73005EF (8-[2-(2,3-dihydro-1,4-benzodioxin-2-yl)methylamino]-8- azaspiro[4,5]decan-7,9-dione methyl sulphonate), a novel selective 5-HT1A receptor ligand with putative anxiolytic properties, were explored using models of central pre- and postsynaptic 5-HT1A receptor function in the male rat. MDL 73005EF dose dependently decreased the hippocampal 5-HT output measured by in vivo microdialysis in chloral hydrate-anaesthetised rats and this response was antagonised by the 5-HT1A/B receptor antagonist, pindolol. Local administration of MDL 73005EF had no effect on the hippocampal 5-HT output. MDL 73005EF failed to alter basal plasma adrenocorticotropin (ACTH) levels but, in common with pindolol, attenuated the ACTH response to the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). In contrast to 8-OH-DPAT, MDL 73005EF significantly increased plasma prolactin but apparently not through a 5-HT receptor-mediated mechanism. The results indicate that MDL 73005EF possesses mixed 5-HT1A receptor agonist/antagonist properties, acting as an agonist at presynaptic 5-HT1A receptors controlling 5-HT release and as an antagonist at postsynaptic 5-HT1A receptors mediating ACTH release.
- Published
- 1990
62. Stereoselectivity of Drug Receptor Interactions
- Author
-
Uli Hacksell, Anders Karlén, Stephan Hjorth, L.-E. Arvidsson, Anette M. Johansson, and Kristina Luthman
- Subjects
Chemistry ,Public Health, Environmental and Occupational Health ,Pharmacology (nursing) ,D1-like receptor ,Pharmacology ,D2-like receptor ,Dopamine receptor ,Dopamine receptor D3 ,Drug Guides ,Dopamine receptor D2 ,Drug receptor ,Pharmacology (medical) ,Receptor ,Endogenous agonist - Abstract
Recent results in studies of interactions between dopamine receptors and stereoselec tive agonists and antagonists are reviewed. Also discussed are the stereoselectivity of serotonergic 5-HT1A-receptor agonists and some of the difficulties associated with modeling the interaction between ligands and receptors on a molecular level.
- Published
- 1990
63. Effects of 5-HT and 8-OH-DPAT on forebrain monoamine synthesis after local application into the median and dorsal raphe nuclei of the rat
- Author
-
Stephan Hjorth, Sven Ahlenius, and Viveka Hillegaart
- Subjects
Male ,Serotonin ,medicine.medical_specialty ,Tetrahydronaphthalenes ,Population ,Naphthalenes ,Nucleus accumbens ,Biology ,5-Hydroxytryptophan ,Catecholamines ,Dorsal raphe nucleus ,Internal medicine ,Basal ganglia ,medicine ,Animals ,Enzyme Inhibitors ,education ,Biological Psychiatry ,8-Hydroxy-2-(di-n-propylamino)tetralin ,education.field_of_study ,Olfactory tubercle ,Rats, Inbred Strains ,Anatomy ,Dihydroxyphenylalanine ,Frontal Lobe ,Rats ,Psychiatry and Mental health ,Hydrazines ,Globus pallidus ,Endocrinology ,nervous system ,Neurology ,Forebrain ,Raphe Nuclei ,Neurology (clinical) ,Raphe nuclei - Abstract
5-HT (10 and 40 micrograms) and 8-OH-DPAT (1 and 5 micrograms) were locally applied into the dorsal or median raphe nuclei in awake, unrestrained, rats. All animals were also treated with the 5-HTP and DOPA decarboxylase inhibitor NSD-1015, 100 mg kg-1 SC, 30 min before decapitation. 5-HT or 8-OH-DPAT were administered 5 min before NSD-1015. The regional brain in vivo rate of tyrosine and tryptophan hydroxylase activity was estimated by measuring the accumulation of DOPA and 5-HTP. The following brain regions were sampled: neocortex, hippocampus, dorso-lateral neostriatum, ventro-medial neostriatum, nucleus accumbens, olfactory tubercle, globus pallidus, septum and the amygdala. Compared to normal controls, there were small and inconsistent effects on forebrain 5-HTP accumulation by saline injections into the dorsal or the median raphe (an increase in 3 out of 36 experiments), whereas strong effects by the injection procedure were noted on forebrain DOPA accumulation (an increase in 15 out of 36 experiments). Injections of 5-HT (same effect by 10 or 40 micrograms) into the dorsal raphe, produced a decrease in 5-HTP accumulation in all forebrain areas except for the hippocampus and the septum, whereas no effects were seen in any area after median raphe injections. In contrast, 8-OH-DPAT preferentially produced a decrease in forebrain 5-HTP accumulation after median raphe injections and less, but statistically significant effects by dorsal raphe injections. The 8-OH-DPAT injection into the median raphe primarily affected limbic forebrain areas (hippocampus, nucleus accumbens, ventro-medial neostriatum, amygdala and the septum). This dissociation of the effects of 5-HT and 8-OH-DPAT on forebrain 5-HT synthesis after local application into the dorsal or the median raphe strongly supports the contention of heterogeniety in the brain 5-HT receptor population in terms of receptor subtypes and/or receptor regulation.
- Published
- 1990
64. Pharmacological profiling of the hemodynamic effects of cannabinoid ligands: a combined in vitro and in vivo approach
- Author
-
Anna Lindblom, Annika Åstrand, Cherry L. Wainwright, Sarah K. Walsh, Stephen J. Leslie, Claire Y. Hepburn, Stephan Hjorth, Peter J. Greasley, Erik Ryberg, and Oliver Keown
- Subjects
AM251 ,Agonist ,CB1 receptor ,Cannabinoid receptor ,Cannabinoids ,medicine.drug_class ,medicine.medical_treatment ,Antagonist ,Original Articles ,Biology ,Pharmacology ,hemodynamics ,G protein coupled receptor 55 ,Neurology ,GPR55 ,medicine ,lipids (amino acids, peptides, and proteins) ,Cannabinoid ,General Pharmacology, Toxicology and Pharmaceutics ,Receptor ,Cannabidiol ,medicine.drug - Abstract
The receptors mediating the hemodynamic responses to cannabinoids are not clearly defined due to the multifarious pharmacology of many commonly used cannabinoid ligands. While both CB1 and TRPV1 receptors are implicated, G protein-coupled receptor 55 (GPR55) may also mediate some of the hemodynamic effects of several atypical cannabinoid ligands. The present studies attempted to unravel the pharmacology underlying the in vivo hemodynamic responses to ACEA (CB1 agonist), O-1602 (GPR55 agonist), AM251 (CB1 antagonist), and cannabidiol (CBD; GPR55 antagonist). Agonist and antagonist profiles of each ligand were determined by ligand-induced GTPγS binding in membrane preparations expressing rat and mouse CB1 and GPR55 receptors. Blood pressure responses to ACEA and O-1602 were recorded in anesthetized and conscious mice (wild type, CB1 (-/-) and GPR55(-/-)) and rats in the absence and presence of AM251 and CBD. ACEA demonstrated GTPγS activation at both receptors, while O-1602 only activated GPR55. AM251 exhibited antagonist activity at CB1 and agonist activity at GPR55, while CBD demonstrated selective antagonist activity at GPR55. The depressor response to ACEA was blocked by AM251 and attenuated by CBD, while O-1602 did not induce a depressor response. AM251 caused a depressor response that was absent in GPR55(-/-) mice but enhanced by CBD, while CBD caused a small vasodepressor response that persisted in GPR55(-/-) mice. Our findings show that assessment of the pharmacological profile of receptor activation by cannabinoid ligands in in vitro studies alongside in vivo functional studies is essential to understand the role of cannabinoids in hemodynamic control.
- Published
- 2015
65. Effect of halving the dose of venlafaxine to adjust for putative pharmacokinetic and pharmacodynamic changes in an animal model of chronic hepatic encephalopathy
- Author
-
Finn Bengtsson, Cecilia Wikell, Gustav Apelqvist, Fredrik C. Kugelberg, and Stephan Hjorth
- Subjects
Male ,medicine.medical_specialty ,Serotonin ,Dopamine ,Microdialysis ,Encephalopathy ,Portacaval ,Rats, Sprague-Dawley ,Norepinephrine ,Pharmacokinetics ,Internal medicine ,Monoaminergic ,medicine ,Animals ,Pharmacology (medical) ,Hepatic encephalopathy ,Biotransformation ,Pharmacology ,Brain Chemistry ,Dose-Response Relationship, Drug ,business.industry ,Venlafaxine Hydrochloride ,medicine.disease ,Cyclohexanols ,Rats ,Disease Models, Animal ,Endocrinology ,Hepatic Encephalopathy ,Toxicity ,Ven ,Chronic Disease ,Neurology (clinical) ,business ,Selective Serotonin Reuptake Inhibitors ,Half-Life - Abstract
Patients with chronic hepatic encephalopathy display monoaminergic perturbations together with affective symptoms. Thus, these patients belong to a group with a probability of receiving antidepressant drug treatment. The liver impairment may result in pharmacokinetic alterations of the antidepressant drug, which in turn may affect the already perturbed monoaminergic function. Venlafaxine (VEN) was administered as a single subcutaneous challenge to portacaval shunted (experimental hepatic encephalopathy model) rats (5 mg/kg) and sham-operated rats (5 and 10 mg/kg). The aims were to investigate whether a reduced dose in portacaval shunted rats resulted in higher concentrations of VEN and serotonin as compared to control rats, which had been demonstrated earlier when the rats received the same dose (10 mg/kg). A 50% reduction of the dose of VEN administered to portacaval shunted rats resulted in elevated levels of VEN in serum, brain parenchyma, and brain dialysate about 300 minutes after the injection. The VEN challenge increased the serotonin and noradrenaline concentrations in dialysate in portacaval shunted rats and both sham groups, but the three VEN groups did not differ in any major way in serotonin and noradrenaline output. Therefore, when the dose of VEN administered to experimental hepatic encephalopathy was reduced 50% as compared to control rats, mainly pharmacokinetic, and possibly also monoaminergic, alterations were observed.
- Published
- 2002
66. Local infusion of the selective 5HT-1B agonist CP-93,129 facilitates striatal dopamine release in vivo
- Author
-
Matthew P. Galloway, Michael J. Keegan, Stephan Hjorth, and Camille S. Suchowski
- Subjects
Male ,Striatal dopamine ,Agonist ,Pyridines ,medicine.drug_class ,Chemistry ,Dopamine ,In Vitro Techniques ,Pharmacology ,Corpus Striatum ,Rats ,Serotonin Receptor Agonists ,Rats, Sprague-Dawley ,Cellular and Molecular Neuroscience ,In vivo ,Receptors, Serotonin ,medicine ,Animals ,Infusions, Parenteral ,Pyrroles ,5-HT receptor - Published
- 1993
67. Effect of citalopram on brain serotonin release in experimental hepatic encephalopathy: implications for thymoleptic drug safety in liver insufficiency
- Author
-
Stephan Hjorth, Finn Bengtsson, Cecilia Wikell, Peter B. F. Bergqvist, and Gustav Apelqvist
- Subjects
Male ,medicine.medical_specialty ,Serotonin ,Injections, Subcutaneous ,Microdialysis ,Encephalopathy ,Neocortex ,Citalopram ,Reuptake ,Injections ,Potassium Chloride ,Rats, Sprague-Dawley ,Pharmacokinetics ,Internal medicine ,medicine ,Animals ,Pharmacology (medical) ,Hepatic encephalopathy ,Biotransformation ,Pharmacology ,Brain Chemistry ,business.industry ,Hydroxyindoleacetic Acid ,medicine.disease ,Antidepressive Agents ,Rats ,Endocrinology ,Hepatic Encephalopathy ,Systemic administration ,Autoreceptor ,Neurology (clinical) ,Reuptake inhibitor ,business ,Extracellular Space ,Selective Serotonin Reuptake Inhibitors ,medicine.drug - Abstract
In the present study, effects of citalopram (CIT) on brain 5-hydroxytryptamine (5-HT) release in experimental chronic hepatic encephalopathy (HE) were investigated. Neocortical administration of CIT (1.0 microM) increased the brain 5-HT output to a similar extent in portacaval shunted (PCS) rats and sham-operated controls, indicating that a previous described mismatch between increased 5-HT turnover and unchanged release in PCS rats is not explained by an accelerated brain 5-HT reuptake. Subsequent systemic administration of CIT (5 mg/kg subcutaneously) resulted in a more pronounced attenuation of the brain 5-HT release in PCS rats than in sham-operated controls, possibly indicating a higher susceptibility to indirect mid-brain 5-HT1A autoreceptor activation in experimental portal-systemic encephalopathy (PSE). A KCl (60 mM) challenge in the presence of locally administered CIT (1 microM) induced a more marked neocortical 5-HT response in PCS rats than in sham-operated controls, confirming previous results of a higher than normal amount of 5-HT available for depolarization-induced release in PCS rats. Although the pharmacodynamic parameters in this study was investigated for CIT, the likelihood of a parallel pharmacokinetic alteration existing for this drug in the PCS condition also was indicated. It is thus suggested that otherwise generally safe central nervous system 5-HT-active drugs may represent a potential hazard in patients with liver failure with or without PSE.
- Published
- 1997
68. Effects of Ammonia and L-Tryptophan Loading on Brain Extracellular 5-HT and 5-HIAA Levels in Chronic Experimental Hepatic Encephalopathy
- Author
-
Finn Bengtsson, Roger F. Butterworth, R. M. Audet, Stephan Hjorth, Peter B. F. Bergqvist, and Gustav Apelqvist
- Subjects
medicine.medical_specialty ,Chemistry ,Tryptophan ,Metabolism ,medicine.disease ,Pathogenesis ,chemistry.chemical_compound ,Endocrinology ,In vivo ,Internal medicine ,medicine ,Aromatic amino acids ,Extracellular ,Hepatic encephalopathy ,5-HT receptor - Abstract
Hepatic encephalopathy (HE) refers to a neuropsychiatric syndrome observed in patients with chronic liver failure. The pathogenesis for this important, but clinically often neglected, syndrome is still unknown. A profound perturbation in the handling of ammonia as well as of the essential aromatic amino acid L-tryptophan (L-TRP) has been shown to be associated with HE. This incapacity for normal L-TRP processing accompanying HE in vivo encompasses disturbances in L-TRP kinetics and metabolism both in brain tissue (1, for overview, see 2) as well as in the brain extracellular compartment (3,4).
- Published
- 1997
69. Raphe 5-HT1A autoreceptors, but not postsynaptic 5-HT1A receptors or beta-adrenoceptors, restrain the citalopram-induced increase in extracellular 5-hydroxytryptamine in vivo
- Author
-
Stephan Hjorth, Stéphane Milano, and H. Jörgen Bengtsson
- Subjects
Male ,medicine.medical_specialty ,Serotonin ,medicine.drug_class ,Pyridines ,Microdialysis ,Adrenergic beta-Antagonists ,Stimulation ,Biology ,Citalopram ,Hippocampus ,Piperazines ,Propanolamines ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Postsynaptic potential ,Internal medicine ,Receptors, Adrenergic, beta ,medicine ,Animals ,Neurotransmitter ,Pharmacology ,Raphe ,Receptor antagonist ,Betaxolol ,Rats ,Endocrinology ,nervous system ,chemistry ,Receptors, Serotonin ,5-HT1A receptor ,Raphe Nuclei ,Serotonin Antagonists ,Penbutolol ,Raphe nuclei ,Extracellular Space ,Receptors, Serotonin, 5-HT1 ,Selective Serotonin Reuptake Inhibitors - Abstract
In vivo microdialysis in rat ventral hippocampus was used (i) to verify the importance of 5-HT1A autoreceptors in the raphe as targets for drugs that enhance the citalopram-induced elevation of forebrain 5-hydroxytryptamine (5-HT), and (ii) to further examine the specificity of (−)-penbutolol in this regard. The selective 5-HT1A receptor antagonist WAY100635 (s.c., or intra-raphe) or the mixed 5-HT 1A 1B β- adrenoceptor antagonist (−)-penbutolol (s.c.), potentiated the citalopram-induced 5-HT rise, whereas local ‘reverse’ dialysis of WAY100635 into the ventral hippocampus did not. Furthermore, the (−)-penbutolol-induced augmentation proved stereoselective and not mediated by β-adrenoceptors (no effect of s.c. (+)-penbutolol, or β1- and β2-adrenoceptor blockers (betaxolol, ICI118.551)). These data provide direct evidence that increased stimulation of 5-HT1A autoreceptors in the midbrain raphe impedes the effect of citalopram on forebrain extracellular 5-HT, whereas neither postsynaptic 5-HT1A receptors nor β-adrenoceptors appear to be involved.
- Published
- 1996
70. 11-substituted (R)-aporphines: synthesis, pharmacology, and modeling of D2A and 5-HT1A receptor interactions
- Author
-
Anette M. Johansson, Johanna M. Jansen, Stephan Hjorth, Martin H. Hedberg, Gunnar Nordvall, Tero Linnanen, and Lena Unelius
- Subjects
Steric effects ,Sulfonyl ,chemistry.chemical_classification ,Male ,Trifluoromethyl ,Stereochemistry ,Receptors, Dopamine D2 ,Substituent ,Combinatorial chemistry ,Chemical synthesis ,Rats ,Serotonin Receptor Agonists ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Structure-Activity Relationship ,chemistry ,Receptors, Serotonin ,Drug Discovery ,Dopamine Agonists ,Molecular Medicine ,Animals ,Humans ,Serotonin ,Aporphine ,Receptor - Abstract
A series of C11-substituted (R)-aporphines and C11-oxygenated (R)-noraporphines has been synthesized and evaluated for central serotonergic and dopaminergic effects in vitro and in vivo. The various C11-substituents were introduced using efficient nickel- and palladium-catalyzed reactions of the corresponding triflate (R)-11-[[(trifluoromethyl)sulfonyl]oxy]aporphine (6). Several compounds display high affinity to serotonin 5-HT1A receptors in spite of major differences in steric bulk and electronic properties of the various C11-substituents. A change of the N-methyl group of the nonselective 3 to H [23, (R)-11-hydroxynoraporphine] or propyl [2, (R)-11-hydroxy-N-propylnoraporphine] increases the selectivity for 5-HT1A receptors (100-fold) and dopamine D2A receptors (3-fold), respectively. Compounds 3 and 23 have similar affinities to 5-HT1A receptors, whereas the propyl substituent of 2 not only enhances the selectivity for D2A receptors but also increases the D2A affinity. Modeling of ligand-receptor binding site interactions yielded an interaction site model for the 5-HT1A receptor that describes a gradual change in binding mode for C11-hydroxy, -methoxy-, and -phenyl-substituted derivatives. Hydrogen bonding is hereby gradually replaced by van der Waals interactions involving a relatively large lipophilic pocket. The derived D2A receptor model can accommodate both the N-propyl substituent of 2 and the C11-ethyl substituent of 11 [(R)-11-ethylaporphine].
- Published
- 1996
71. 10-substituted 11-oxygenated (R)-aporphines: synthesis, pharmacology, and modeling of 5-HT1A receptor interactions
- Author
-
Stephan Hjorth, Martin H. Hedberg, Gunnar Nordvall, Johanna M. Jansen, Anette M. Johansson, and Lena Unelius
- Subjects
Steric effects ,Agonist ,Male ,Models, Molecular ,medicine.drug_class ,Chemistry ,Stereochemistry ,Aporphines ,Chemical synthesis ,Combinatorial chemistry ,Affinities ,Rats ,Serotonin Receptor Agonists ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,Receptors, Serotonin ,Drug Discovery ,medicine ,Molecular Medicine ,5-HT1A receptor ,Animals ,Humans ,Serotonin ,Receptor - Abstract
Derivatives of the selective serotonin 5-HT1A receptor agonist (R)-11-hydroxy-10-methylaporphine (2) having various substituents in the C10-position or at the nitrogen have been synthesized from natural morphine or 6-O-acetylcodeine, respectively. The C10-substituents were introduced using efficient Stille or Suzuki cross-coupling reactions. The compounds were evaluated for their affinities to 5-HT1A and dopamine (DA) D1 and D2A receptors in vitro. All compounds tested displayed low (micromolar) affinities to D1 and D2A receptors. In addition, changes in steric bulk and/or electronic properties of the C10-substituent as compared to a C10-methyl group, as well as substitution of the N-methyl group for a hydrogen or a larger N-alkyl group, produced a marked decrease in the affinities to 5-HT1A receptors. Selected compounds that displayed moderate to high affinities to 5-HT1A receptors were evaluated for their ability to stimulate 5-HT1A receptors in vivo. The evaluated compounds behaved as agonists at 5-HT1A receptors, except for the N-propyl analogue of 2, (R)-11-hydroxy-10-methyl-N-propylnoraporphine (23), which displayed weak DA receptor agonism at the doses tested. Hence, the substitution pattern of 2 (a C10-methyl, a C11-hydroxy, and an N-methyl group) appears to be optimal for potent interaction of 10,11-disubstituted (R)-aporphines with 5-HT1A receptors. Modeling of ligand-5-HT1A receptor interactions was performed in an attempt to rationalize the observed affinity data. The binding site model suggests the presence of a "methyl pocket" in the 5-HT1A receptor binding ste. The C11-methoxy-substituted aporphines appear to have a different binding mode compared to 2, implying a different accessibility of these compounds to the "methyl pocket".
- Published
- 1996
72. Effect of chronic administration of the selective serotonin (5-HT) uptake inhibitor citalopram on extracellular 5-HT and apparent autoreceptor sensitivity in rat forebrain in vivo
- Author
-
Stephan Hjorth and Sidney B. Auerbach
- Subjects
Male ,Agonist ,Serotonin ,medicine.medical_specialty ,Microdialysis ,Indoles ,Pyridines ,medicine.drug_class ,Chloral hydrate ,Citalopram ,Pharmacology ,behavioral disciplines and activities ,Rats, Sprague-Dawley ,Prosencephalon ,Internal medicine ,mental disorders ,medicine ,Extracellular ,Animals ,Pyrroles ,Infusions, Intravenous ,5-HT receptor ,Autoreceptors ,Analysis of Variance ,Chemistry ,Drug Tolerance ,General Medicine ,Antidepressive Agents ,Rats ,Serotonin Receptor Agonists ,Endocrinology ,Autoreceptor ,Raphe Nuclei ,Dialysis ,Selective Serotonin Reuptake Inhibitors ,medicine.drug - Abstract
Rats were administered the selective serotonin (5-HT) uptake blocker citalopram or saline for 14 days to determine if prolonged treatment would lead to changes in extracellular 5-HT or autoreceptor sensitivity. One day after drug withdrawal, dialysis probes were implanted in the frontal cortex and dorsal hippocampus. Dialysis experiments were carried out using chloral hydrate anesthetized rats. The experimental protocol comprised the administration of three consecutive drug challenges: (1) After stable baseline levels were obtained, citalopram was infused through the dialysis probes to locally block uptake in the forebrain. (2) Subsequently, a 5-HT1B receptor agonist (RU24969 or CP93,129) was infused through the probe to test for changes in terminal autoreceptor sensitivity. (3) Last, citalopram was administered systemically to test the effect of indirect activation of somatodendritic autoreceptors. Under these conditions, with uptake already blocked locally in the forebrain, systemic citalopram produces a decrease in extracellular 5-HT, an effect that can be inhibited by pretreatment with antagonists of 5-HT1A receptors. The results indicate that during local infusion of citalopram extracellular 5-HT was significantly higher in the dorsal hippocampus of the chronic citalopram as compared to saline treatment group. This difference persisted throughout the full time course of the experiment. However, the decreases in 5-HT levels produced by local infusion of a 5-HT1B receptor agonist or after systemic citalopram administration were not significantly different between the chronic citalopram and saline treated groups. There were no significant differences between chronic citalopram and saline treated animals in frontal cortex. These results suggest that prolonged inhibition of 5-HT uptake may produce a selective change in the regulation of release from median raphe 5-HT neurons, but this change could not be clearly linked to a change in nerve terminal or somatodendritic autoreceptor sensitivity.
- Published
- 1995
73. Studies on the role of 5-HT1A autoreceptors and alpha 1-adrenoceptors in the inhibition of 5-HT release--I. BMY7378 and prazosin
- Author
-
Stephan Hjorth, H.J. Bengtsson, J.F. Lundberg, Stéphane Milano, and Trevor Sharp
- Subjects
Agonist ,Male ,medicine.medical_specialty ,Serotonin ,Time Factors ,medicine.drug_class ,Microdialysis ,Pharmacology ,Partial agonist ,Hippocampus ,Piperazines ,Rats, Sprague-Dawley ,Cellular and Molecular Neuroscience ,Internal medicine ,Receptors, Adrenergic, alpha-1 ,polycyclic compounds ,medicine ,Prazosin ,Animals ,heterocyclic compounds ,Pindolol ,5-HT receptor ,Dose-Response Relationship, Drug ,Chemistry ,musculoskeletal, neural, and ocular physiology ,Antagonist ,Rats ,Endocrinology ,nervous system ,Receptors, Serotonin ,Autoreceptor ,5-HT1A receptor ,medicine.drug - Abstract
The present study utilized in vivo microdialysis to investigate the importance of 5-HT1A autoreceptors and alpha 1-adrenoceptors in the decreased 5-HT release obtained following administration of the mixed 5-HT1A autoreceptor partial agonist/alpha 1-adrenoceptor antagonist BMY7378, the selective 5-HT1A receptor agonist 8-OH-DPAT and the alpha 1-adrenoceptor antagonist prazosin. BMY7378 (0.25 mg/kg, s.c.), 8-OH-DPAT (0.025 mg/kg, s.c.) and prazosin (0.1-1.0 mg/kg, s.c.) all suppressed ventral hippocampal 5-HT efflux. The BMY7378- and 8-OH-DPAT-induced inhibition of 5-HT release were reversed by a 40 min pre-treatment with either (+/-)pindolol (8 mg/kg, s.c.) or WAY-100635 (0.3 mg/kg, s.c.), to block 5-HT1A autoreceptors. Neitehr of these antagonists altered the prazosin-induced (0.3 mg/kg, s.c.) 5-HT disease.(i) confirm that both an alpha 1-adrenoceptor antagonist (prazosin) and 5-HT1A autoreceptor stimulants (BMY7378 and 8-OH-DPAT) may reduce cerebral 5-HT release; (ii) support that the BMY7378-induced decrease in 5-HT release results from 5-HT1A autoreceptor agonism, rather than alpha 1-adrenoceptor blockade; and (iii) argue against "physiological" antagonism (i.e. via blockade of beta-adrenoceptors, 5-HT1B receptors or some other mechanism) as an explanation for the reversal by pindolol of 5-HT1A autoreceptor agonist-induced suppression of 5-HT release. These data support the usefulness of pindolol, as well as the more specific compound WAY-100635, to block 5-HT1A autoreceptors.
- Published
- 1995
74. Changes in the acoustic startle response and prepulse inhibition of acoustic startle in rats after local injection of pertussis toxin into the ventral tegmental area
- Author
-
Lennart Svensson, Jörgen A. Engel, Jianhua Zhang, and Stephan Hjorth
- Subjects
Agonist ,Male ,medicine.medical_specialty ,Startle response ,Reflex, Startle ,Time Factors ,Apomorphine ,medicine.drug_class ,Rats, Sprague-Dawley ,Internal medicine ,Moro reflex ,medicine ,Animals ,Virulence Factors, Bordetella ,Amphetamine ,Prepulse inhibition ,Pharmacology ,8-Hydroxy-2-(di-n-propylamino)tetralin ,medicine.diagnostic_test ,Chemistry ,Ventral Tegmental Area ,Rats ,Ventral tegmental area ,medicine.anatomical_structure ,Endocrinology ,Acoustic Stimulation ,Pertussis Toxin ,5-HT1A receptor ,Dialysis ,medicine.drug - Abstract
The effect of local injection of pertussis toxin (PTX) into the ventral tegmental area (VTA) on acoustic startle in rats was investigated. The PTX treatment caused only minor effects of its own on the acoustic startle response (ASR) or prepulse inhibition (PPI) of acoustic startle. However, systemic treatment with the indirect DA receptor agonist, amphetamine (2 mg/kg, SC) caused a significant increase in ASR magnitude and a significant disruption of PPI in PTX-treated rats while no such effects were observed in sham-treated rats. Treatment with the direct DA receptor agonist, apomorphine (2 mg/kg, SC), caused a significant disruption of PPI, an effect that was observed in both PTX- and sham-treated rats. Treatment with the 5-HT1A receptor agonist, 8-OH-DPAT (0.5 mg/kg, SC), did not affect PPI in either group but caused a marked increase in ASR magnitude in sham-treated rats. Interestingly, this effect was blocked in PTX-treated rats. The present results suggest that local injection of PTX into the VTA causes an increased sensitivity to the behavioural effects of psychostimulants on acoustic startle and may also suggest that intact midbrain 5-HT1A receptors are essential for the effect of 5-HT1A agonists on acoustic startle.
- Published
- 1995
75. Evidence for 5-HT autoreceptor-mediated, nerve impulse-independent, control of 5-HT synthesis in the rat brain
- Author
-
Camille S. Suchowski, Matthew P. Galloway, and Stephan Hjorth
- Subjects
Male ,Serotonin ,Reserpine ,Brain ,Pharmacology ,Biology ,Serotonergic ,Denervation ,Piperazines ,Rats ,Serotonin Receptor Agonists ,Rats, Sprague-Dawley ,Cellular and Molecular Neuroscience ,Monoamine neurotransmitter ,In vivo ,Receptors, Serotonin ,medicine ,Autoreceptor ,Animals ,Cyanopindolol ,5-HT receptor ,medicine.drug ,Autoreceptors - Abstract
To gain further insight into the operation of 5-HT autoreceptor-mediated feedback control of 5-HT biosynthesis in serotonergic nerve terminal areas, the effect of the 5-HT1B and the 5-HT1A receptor agonists, TFMPP and 8-OH-DPAT, respectively, were investigated in the rat central nervous system (CNS) using in vivo and in vitro neurochemical approaches. TFMPP suppressed 5-HT synthesis (5-HTP accumulation after decarboxylase inhibition) both in vivo and in vitro. In vivo, the 5-HT synthesis-suppressing effect of the drug (3.0 mg/kg, s.c.) proved resistant to either acute hemitransection or reserpine (5 mg/kg, i.p.; 90 min before) pretreatment. In vitro, in cortical, hippocampal and striatal slice preparations, TFMPP (0.1-10 microM) decreased 5-HT synthesis under basal and stimulated (30 mM K+) conditions, an effect which was unaltered by prior in vivo reserpine-induced 5-HT depletion but was attenuated in the presence of 5-HT1B receptor antagonists such as methiothepin, cyanopindolol or propranolol. The 8-OH-DPAT (0.1 mg/kg, s.c.)-induced decrease of 5-HT synthesis in vivo was abolished by hemitransection but resistant to acute reserpine pretreatment; 8-OH-DPAT (10 microM) did not decrease 5-HT synthesis in vitro. In conclusion, the present study confirms the importance of 5-HT autoreceptors in the feedback control of nerve terminal 5-HT biosynthesis. Specifically, our data indicate: (1) that the reduction of rat brain 5-HT synthesis after TFMPP is mediated by 5-HT1B autoreceptors located on the serotonergic axon terminals, and (2) that the effect is directly mediated and occurs independently of 5-HT neuronal firing and intact monoamine stores.
- Published
- 1995
76. Neocortical dialysate monoamines of rats after acute, subacute, and chronic liver shunt
- Author
-
Finn Bengtsson, D. K. Bosman, Robert A. F. M. Chamuleau, Peter B. F. Bergqvist, M. Maas, B.A.P.M. Vogels, and Stephan Hjorth
- Subjects
Male ,medicine.medical_specialty ,Microdialysis ,Serotonin ,Dopamine ,Phenylalanine ,Biology ,Biochemistry ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Norepinephrine ,Ammonia ,Biogenic amine ,Internal medicine ,medicine ,Extracellular ,Animals ,Biogenic Monoamines ,Amino Acids ,Rats, Wistar ,Neurotransmitter ,chemistry.chemical_classification ,Cerebral Cortex ,Body Weight ,Tryptophan ,Hydroxyindoleacetic Acid ,Rats ,Disease Models, Animal ,Endocrinology ,Monoamine neurotransmitter ,nervous system ,chemistry ,Hepatic Encephalopathy ,Acute Disease ,Chronic Disease ,3,4-Dihydroxyphenylacetic Acid ,Tyrosine ,Extracellular Space ,Dialysis ,medicine.drug - Abstract
Intracerebral microdialysis was applied to monitor the neocortical extracellular levels of the aromatic amino acids phenylalanine, tyrosine, and tryptophan, the neurotransmitters dopamine (DA), noradrenaline (NA), and serotonin (5-HT), and the metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindole-3-acetic acid (5-HIAA) in rats with various forms of experimental hepatic encephalopathy (HE). The extracellular aromatic amino acid levels were clearly increased in acute, subacute, and chronic HE. No changes compared with controls in the neocortical DA release could be detected in the three experimental HE rat models investigated. The NA release showed a significant increase only in the subacute HE group. These data suggest that HE may not be associated with any major reduction of neocortical DA or NA release as previously suggested. In acute and subacute HE, decreased extracellular DOPAC but elevated 5-HIAA concentrations were seen. In chronic HE, elevations of both DOPAC and 5-HIAA were observed. Neocortical 5-HT release did not change in subacute and chronic HE, whereas it decreased in acute HE compared with control values. Significant increase in extracellular concentrations of 5-HIAA and of the 5-HIAA/5-HT ratio in the present study are in agreement with previously reported increases in 5-HT turnover in experimental HE. However, a substantially increased 5-HT turnover in experimental HE does not appear to be related to an increase in neuronal neocortical 5-HT release.
- Published
- 1995
77. Catecholamine-Containing Biodegradable Microsphere Implants: An Overview of Experimental Studies in Dopamine-Lesioned Rats
- Author
-
Annica B. Dahlstrom, Thomas R. Tice, Stephan Hjorth, Eng-Ang Ling, Amanda McRae, and David W. Mason
- Subjects
business.industry ,Oculogyric crisis ,Biodegradable microsphere ,Central nervous system ,Pharmacology ,medicine.disease ,Lesion ,Neurochemical ,medicine.anatomical_structure ,Dopamine ,Current medication ,Catecholamine ,Medicine ,medicine.symptom ,business ,medicine.drug - Abstract
The main neurochemical characteristic of Parkinson’s disease (PD) is a marked lesion of the nigro-striatal dopamine pathway. In attempts to provide dopamine replacement therapy to Parkinson’s patients, the current medication is L-DOPA (Birkmayer and Hornykiewicz, 1961). Dopamine (DA) itself cannot be taken orally because it will not reach the brain. Unfortunately, L-DOPA can cause serious adverse reactions and its effectiveness decreases with time. For these reasons, there has been an increasing demand for and interest in novel techniques for site-directed delivery of substances into the central nervous system (CNS) (Stahl, 1984).
- Published
- 1995
78. (R)-11-Hydroxy- and (R)-11-Hydroxy-10-methylaporphine:Synthesis, pharmacology, and modeling of D2A and 5-HT1A receptor interactions
- Author
-
Stephan Hjorth, Arnold R. Martin, Lena Unelius, Uli Hacksell, Martin H. Hedberg, S. Sundell, Anette M. Johansson, Hong Bing Li, Gunnar Nordvall, and Ari Yliniemela
- Subjects
Agonist ,Male ,Aporphines ,medicine.drug_class ,Stereochemistry ,Microdialysis ,Pharmacology ,Serotonergic ,Crystallography, X-Ray ,Partial agonist ,Rats, Sprague-Dawley ,In vivo ,Drug Discovery ,medicine ,Computer Graphics ,Animals ,Humans ,Binding site ,Receptor ,Chemistry ,Receptors, Dopamine D2 ,Colforsin ,Biological activity ,Rats ,Serotonin Receptor Agonists ,Enzyme Activation ,Molecular Medicine ,5-HT1A receptor ,Adenylyl Cyclases - Abstract
(R)-11-Hydroxyaporphine (2) and (R)-11-hydroxy-10-methylaporphine (3) were synthesized from natural morphine by using new, short, and efficient synthetic sequences. The dopaminergic and serotonergic effects of 2 and 3 were evaluated by use of in vitro and in vivo test systems. The results indicate that 3 is a potent, selective, and efficacious 5-HT1A receptor agonist. In contrast, 2 is a partial 5-HT1A receptor agonist of low potency which has affinity also for central D1 and D2A receptors. The differences in pharmacological profiles were rationalized by modeling of ligand-receptor interactions using homology-based receptor models of the 5-HT1A and D2A receptor binding site. The selective and pronounced serotonergic effects of 3 appear to be due to the C10-methyl group, which is accommodated by a lipophilic pocket in the 5-HT1A receptor. In contrast, the C10-methyl group of 3 is not accommodated by the binding site model of the D2A receptor.
- Published
- 1995
79. Catecholamine-containing biodegradable microsphere implants as a novel approach in the treatment of CNS neurodegenerative disease. A review of experimental studies in DA-lesioned rats
- Author
-
Annica Dahlström, Thomas R. Tice, Stephan Hjorth, A. McRae, Eng-Ang Ling, and David W. Mason
- Subjects
Male ,Central nervous system ,Neuroscience (miscellaneous) ,Striatum ,Pharmacology ,Lesion ,Rats, Sprague-Dawley ,Cellular and Molecular Neuroscience ,Norepinephrine ,Catecholamines ,Dopamine ,Central Nervous System Diseases ,medicine ,Animals ,Microscopy, Immunoelectron ,Drug Implants ,Tyrosine hydroxylase ,Chemistry ,Immunohistochemistry ,Corpus Striatum ,Microspheres ,Rats ,Apomorphine ,medicine.anatomical_structure ,Neurology ,Catecholamine ,medicine.symptom ,Neuroscience ,medicine.drug - Abstract
Biodegradable controlled-release microsphere systems made with the biocompatible biodegradable polyester excipient poly(DL-lactide-co-glycolide) constitute an exciting new technology for drug delivery to the central nervous system (CNS). Implantable controlled-release microspheres containing dopamine (DA) or norepinephrine (NE) provide a novel means to compare DA- or NE -induced restitution of function in unilateral 6-hydroxydopamine lesioned rats. A suspension of 3 microL of DA- or NE-containing microspheres or empty microspheres was implanted in 2 sites of the DA denervated striatum of rats previously unilaterally lesioned with 6-hydroxydopamine. Contralateral-rotational behavior induced by apomorphine was used as an index of lesion success and, following implantation of the microspheres, also as an index of functional recovery. Interestingly, both DA- and NE-microsphere-implanted rats displayed a 30-50% reduction in the number of apomorphine-induced rotations up to 8 wk postimplantation. Rats implanted with empty microspheres did not demonstrate significant changes in contralateral rotational behavior. Behavioral studies following implantation of a mixture of DA and NE microspheres revealed an 80% decrease in the number of apomorphine induced rotations up to 4 wk. On conclusion of the studies, immunocytochemical examination revealed growth of DA and tyrosine hydroxylase immunoreactive fibers in the striatum of DA and NE microsphere-implanted rats. Functional behavior appeared to correlate with the degree of fiber growth. Preliminary electron microscopic studies showed signs of axonal sprouting in the vicinity of the implanted microspheres. No growth was noted in rats implanted with empty microspheres. This report reviews the abilities of both microencapsulated NE and DA to assure functional recovery and to promote DA fiber (re)growth in parkinsonian rats. This novel means to deliver these substances to the central nervous system could be of therapeutic usefulness in Parkinson's disease.
- Published
- 1994
80. Lack of 5-HT1A autoreceptor desensitization following chronic citalopram treatment, as determined by in vivo microdialysis
- Author
-
Stephan Hjorth and Sidney B. Auerbach
- Subjects
Agonist ,Male ,medicine.medical_specialty ,Microdialysis ,medicine.drug_class ,Pharmacology ,Citalopram ,behavioral disciplines and activities ,Hippocampus ,Rats, Sprague-Dawley ,Cellular and Molecular Neuroscience ,Internal medicine ,mental disorders ,medicine ,Animals ,Brain Chemistry ,Cerebral Cortex ,8-Hydroxy-2-(di-n-propylamino)tetralin ,business.industry ,Rats ,Serotonin Receptor Agonists ,Endocrinology ,Mechanism of action ,Receptors, Serotonin ,Autoreceptor ,Antidepressant ,Raphe Nuclei ,Serotonin ,medicine.symptom ,business ,Reuptake inhibitor ,Selective Serotonin Reuptake Inhibitors ,medicine.drug - Abstract
Electrophysiological studies suggest that 5-HT autoreceptor desensitization may be responsible for the delayed clinical efficacy of some antidepressant drugs, such as selective 5-HT reuptake inhibitors (SSRI) and certain MAO inhibitors (MAOI). In the present study we have used in vivo microdialysis to test this hypothesis. Rats were treated for 2 weeks with the antidepressant SSRI citalopram (5 mg/kg, s.c., b.i.d.). After 24 hr withdrawal, dialysis probes were implanted in the dorsal hippocampus (DH) and the frontal cortex (FCx). The rats then received as acute challenge, a 5-HT1A autoreceptor-active dose of the reference 5-HT1A agonist 8-OH-DPAT (0.025 mg/kg s.c.). The 8-OH-DPAT-induced changes in dialysate 5-HT from the DH and the FCx were monitored and taken as an index of autoreceptor sensitivity. Chronic citalopram and control animals responded similarly to 8-OH-DPAT with a drop of 5-HT of about 50-65%; no significant difference between the chronic citalopram and control groups were obtained, either in the DH or in the FCx. These data suggest that cell body 5-HT1A autoreceptors do not desensitize in response to repeated administration with antidepressant SSRI drugs such as citalopram.
- Published
- 1994
81. Effect of acute and repeated administration of 5-HT1A receptor agonists on 5-HT release in rat brain in vivo
- Author
-
Stephan Hjorth, R. McQuade, Steven R. Bramwell, and Trevor Sharp
- Subjects
Agonist ,Male ,medicine.medical_specialty ,Microdialysis ,Serotonin ,medicine.drug_class ,Adrenergic beta-Antagonists ,Pharmacology ,Hippocampus ,Buspirone ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Pindolol ,Brain Chemistry ,8-Hydroxy-2-(di-n-propylamino)tetralin ,Dose-Response Relationship, Drug ,Chemistry ,8-OH-DPAT ,Ipsapirone ,General Medicine ,Electrodes, Implanted ,Rats ,Serotonin Receptor Agonists ,Electrophysiology ,Endocrinology ,Pyrimidines ,Autoreceptor ,5-HT1A receptor ,medicine.drug - Abstract
1. Electrophysiological measurements of 5-HT neuronal activity report that repeated administration of 5-HT1A receptor agonists leads to desensitization of the 5-HT1A autoreceptor but this has not yet been detected in measurements of brain 5-HT synthesis or metabolism. Here we have determined the effect of repeated administration of 5-HT1A receptor agonists on brain 5-HT release using microdialysis. 2. Acute administration of the 5-HT1A receptor agonists buspirone (0.1–5 mg/kg s.c.) and ipsapirone (0.03–3 mg/kg s.c.) caused a dose-dependent decrease in 5-HT output in ventral hippocampus of the chloral hydrate anaesthetized rat. 3. The 5-HT response to buspirone (0.1 and 0.5 mg/kg s.c.) and ipsapirone (0.3 mg/kg s.c.) was significantly inhibited by pre-treatment with the 5-HT1/β-adrenoceptor antagonist pindolol (8–16 mg/kg s.c.). The 5-HT response to buspirone (0.1 mg/kg s.c.) and ipsapirone (0.3 mg/kg s.c.) was not blocked by pretreatment with a combination of the β1 and β2-adrenoceptor antagonists metoprolol and ICI 118,551 (4 mg/kg s.c.). 4. The effect of an acute challenge of buspirone (0.5 mg/kg s.c.) on 5-HT output in ventral hippocampus was not attenuated in rats treated twice daily for 14 days with 0.5 or 5 mg/kg s.c. buspirone compared to saline-injected controls. Similarly, the decrease in 5-HT induced by an acute challenge of ipsapirone (0.5 mg/kg s.c.) was not attenuated in rats treated twice daily for 14 days with 5 mg/kg s.c. ipsapirone. 5. In further experiments it was shown that the decrease in 5-HT induced in both ventral hippocampus and striatum by an acute challenge of the selective 5-HT1A receptor agonist 8-OH-DPAT (0.025 mg/kg s.c.), was not attenuated in rats treated twice daily for 14 days with 1 mg/kg s.c. 8-OH-DPAT. 6. Basal levels of 5-HT in hippocampal and striatal microdialysates of animals treated repeatedly with the 5-HT1A receptor agonists were not consistently altered relative to treatment controls. 7. In agreement with earlier studies measuring regional brain 5-HT synthesis and metabolism, the present microdialysis measurements of 5-HT release indicate that the inhibitory effect of 5-HT1A receptor agonists on presynaptic 5-HT function is maintained in rats treated repeatedly with the same drugs.
- Published
- 1993
82. The influence of serotoninergic drugs on dopaminergic neurotransmission in rat substantia nigra, striatum and limbic forebrain in vivo
- Author
-
Hans Nissbrandt, Nicholas Waters, and Stephan Hjorth
- Subjects
Agonist ,Male ,medicine.medical_specialty ,medicine.drug_class ,Dopamine ,Substantia nigra ,Ritanserin ,Striatum ,Synaptic Transmission ,Internal medicine ,medicine ,Limbic System ,Animals ,5-HT receptor ,Pharmacology ,Chemistry ,Dopaminergic ,Rats, Inbred Strains ,General Medicine ,Receptor antagonist ,Corpus Striatum ,Rats ,Substantia Nigra ,Endocrinology ,nervous system ,Receptors, Serotonin ,Serotonin Antagonists ,medicine.drug - Abstract
The effects of serotoninergic drugs on dopaminergic neurotransmission in the substantia nigra, the striatum and the limbic forebrain of rat have been investigated. The accumulation of 3-methoxytyramine (3-MT) following inhibition of monoamine oxidase with pargyline was used as an indirect measure of dopamine (DA) activity in vivo. The effects of the following serotoninergic drugs were tested: the 5-HT1A receptor agonist 8-OH-DPAT, the 5-HT1B receptor agonist trifluoromethyl-phenylpiperazine (TFMPP), CGS 12066B and RU 24969, the 5-HT1A/1B antagonist (±)pindolol, the 5-HT2/1C receptor antagonist ritanserin, the 5-HT2/1C receptor agonist DL-1-(2,5-dimethoxy-4-iodo-phenyl)-2-aminopropane (DOI), the 5-HT3 receptor antagonist BRL 43 694, the unselective 5-HT1 receptor antagonist methiothepin, and carbidopa+L-5-hydroxytryptophan (L5-HTP) to achieve a general, unselective stimulation of multiple 5-HT receptors. In the substantia nigra, carbidopa + 5-HTP treatment increased the 3-MT accumulation by 26% and decreased the DA concentration to 67% of controls, tentatively suggesting a 5-HTP-induced displacement of nigral DA. A minor, non dose-related reduction in nigral 3-MT was seen after the 5-HT1A receptor agonist 8-OH-DPAT. None of the other serotonin receptor acting drugs induced any pronounced effect on the nigral 3-MT accumulation. Taken together, the findings provide little support for the idea that one single 5-HT1 receptor subtype serves a modulatory function on DA activity in the substantia nigra. In the striatum and the limbic forebrain, trifluoromethylphenylpiperazine dose-dependently increased the 3-MT accumulation to maximally 200%–220% of controls. In the limbic forebrain also the highest dose of RU 24 969 (15 mg/kg) increased the 3-MT accumulation (78%), whereas in the striatum the lowest does of the drug (1.5 mg/kg) decreased it by 30%. The trifluoromethylphenylpiperazine-induced stimulation of 3-MT accumulation was not blocked by ritanserin. In the limbic forebrain, also DL-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane and carbidopa+Lr5-HTP treatment increased the 3-MT concentrations to 120% and 150% of controls, respectively. Paradoxically, methiothepin also induced an increase of the 3-MT accumulation in these brain regions, probably due to its DA receptor antagonism. None of the other serotoninergic drugs induced any pronounced effects on the 3-MT accumulation in these brain parts. The results may overall support the hypothesis that 5-HT1 does modulate the DA activity in the striatum and limbic forebrain, tentatively via 5-HT1B receptors in the striatum and 5-HT1B and 5-HT2 or 5-HT1C receptors in the limbic forebrain. It may be speculated therefore, that clinical application of 5-HT1 receptor-modulating drugs to influence central dopaminergic activity might be of therapeutical benefit, for example, in motor disorders like Parkinson's disease.
- Published
- 1992
83. Alpha 2-adrenoceptor modulation of rat ventral hippocampal 5-hydroxytryptamine release in vivo
- Author
-
Stephan Hjorth and Rui Tao
- Subjects
Agonist ,Male ,medicine.medical_specialty ,Serotonin ,Tyrosine 3-Monooxygenase ,medicine.drug_class ,Serotonergic ,Hippocampus ,Clonidine ,Dioxanes ,Postsynaptic potential ,Idazoxan ,Internal medicine ,medicine ,Animals ,Pindolol ,Adrenergic alpha-Antagonists ,Pharmacology ,Chemistry ,Antagonist ,Rats, Inbred Strains ,General Medicine ,Receptors, Adrenergic, alpha ,Receptor antagonist ,Rats ,Thiazoles ,Endocrinology ,medicine.drug - Abstract
The putative existence of a functional alpha 2-adrenoceptor-mediated modulation of 5-HT release in vivo from serotonergic neuronal terminals in the ventral hippocampus was investigated using intracerebral microdialysis in chloral hydrate-anaesthetised rats. The alpha 2-adrenoceptor agonist clonidine (0.01-0.3 mg/kg, SC) dose-dependently decreased the 5-HT output. The response to clonidine was antagonized by systemic or local administration of the alpha 2-adrenoceptor antagonist idazoxan (0.1 mg/kg, SC, or 10 mumol/l, via the dialysis perfusion medium). Similarly, the 5-HT release-suppressing response to the thiazole alpha 2-adrenoceptor agonist jingsongling (0.1 mg/kg, SC) was blocked by idazoxan (0.1 mg/kg, SC). The mixed beta-adrenoceptor/5-HT1 receptor antagonist pindolol (8.0 mg/kg, SC) did not affect the clonidine-induced reduction of 5-HT release. Tyrosine hydroxylase inhibition by means of alpha-methyl-para-tyrosine (alpha-MT; 250 mg/kg, IP) caused a drastic reduction (greater than 80%) in dialysate 3,4-dihydroxyphenyl acetic acid (DOPAC) output but did not affect the 5-HT output per se over 3 h post-injection. Nor did the alpha-MT pretreatment prevent, but instead significantly enhanced, the 5-HT release-suppressing effect of clonidine. The results demonstrate that the release of 5-HT from serotonergic nerve terminals in rat ventral hippocampus in vivo is modulated by alpha 2-adrenoceptors, probably both by heteroreceptors on the axon terminals of the serotonergic neurones and by other alpha 2-adrenoceptor sites situated pre- and/or postsynaptic to the noradrenergic terminals. Our results also suggest that while functionally operative, these sites may receive little physiological tone, at least in chloral hydrate-anaesthetised rats.
- Published
- 1992
84. Acute reserpine treatment increases rat brain serotonin synthesis via a nerve impulse-dependent mechanism
- Author
-
Stephan Hjorth
- Subjects
Agonist ,Male ,medicine.medical_specialty ,Serotonin ,Reserpine ,Tetrahydronaphthalenes ,medicine.drug_class ,Central nervous system ,Biochemistry ,Neuronal Transmission ,Cellular and Molecular Neuroscience ,Internal medicine ,medicine ,Animals ,8-Hydroxy-2-(di-n-propylamino)tetralin ,Chemistry ,Brain ,Rats, Inbred Strains ,Denervation ,Rats ,Endocrinology ,medicine.anatomical_structure ,Forebrain ,Autoreceptor ,medicine.drug - Abstract
Notwithstanding recent advances in the understanding of central serotonin (5-HT) function, important basic aspects of the control of brain 5-HT neuronal transmission remain incompletely elucidated. The present experiments addressed the putative mechanism(s) by which acute reserpine treatment stimulates cerebral 5-HT synthesis; also, such studies might shed further light on the relation between impulse flow and transmitter synthesis in central 5-HT neurons. Reserpine (5 mg/kg, i.p., 90 min before death) markedly elevated 5-HT synthesis [5-hydroxytryptophan (5-HTP) accumulation after decarboxylase inhibition by means of NSD 1015] in the limbic, striatal, and cortical rat brain parts. Hemitransection of ascending neuronal connections between the brainstem and the forebrain, performed immediately before reserpine injection, did not affect the 5-HT synthesis per se but completely prevented the drug response on the lesioned side. Similarly, systemic administration of the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (0.1 mg/kg, s.c., 60 min before death) blocked the reserpine-induced elevation of brain 5-HT synthesis. These findings indicate that the reserpine-induced rise in axon terminal 5-HTP accumulation is dependent on intact (5-HT) neuronal impulse flow, which may or may not involve a transient impairment of somatodendritic 5-HT release and, in turn, autoreceptor tone.
- Published
- 1992
85. T1252 The Selective 5-HT1A Antagonist, AZD7371 (Robalzotan Tartrate Monohydrate), Inhibits Pain-Related Visceromotor, But Not Autonomic Cardiovascular, Responses to Colorectal Distension in Rats
- Author
-
Erik Lindström, Håkan Larsson, Vicente Martinez, Mikael Brusberg, Stephan Hjorth, and Anna Ravnefjord
- Subjects
chemistry.chemical_compound ,Hepatology ,chemistry ,business.industry ,Robalzotan ,Gastroenterology ,Antagonist ,Medicine ,Pharmacology ,Tartrate ,business ,Colorectal distension - Published
- 2009
86. Effects of sexual interactions on the in vivo rate of monoamine synthesis in forebrain regions of the male rat
- Author
-
Sven Ahlenius, Viveka Hillegaart, Knut Larsson, and Stephan Hjorth
- Subjects
Male ,medicine.medical_specialty ,Serotonin ,Striatum ,Nucleus Accumbens ,5-Hydroxytryptophan ,Behavioral Neuroscience ,Sexual Behavior, Animal ,Dopamine ,Internal medicine ,Copulation ,medicine ,Animals ,Aromatic Amino Acid Decarboxylase Inhibitors ,Brain Mapping ,Tyrosine hydroxylase ,Chemistry ,Olfactory tubercle ,Ventral striatum ,Brain ,Rats, Inbred Strains ,Tryptophan hydroxylase ,Corpus Striatum ,Dihydroxyphenylalanine ,Rats ,Endocrinology ,Monoamine neurotransmitter ,medicine.anatomical_structure ,Hydrazines ,Dopa Decarboxylase ,Female ,medicine.drug - Abstract
The effects of heterosexual interactions on the in vivo rate of regional brain monoamine synthesis were examined in the male rat. To this end, the animals were administered an inhibitor of cerebral aromatic L-amino acid decarboxylase, NSD-1015 (100 mg.kg-1 i.p.), and regional brain DOPA and 5-HTP accumulation, over a 15-35 min period of sexual interaction, was compared with the DOPA or 5-HTP accumulation in time-matched home cage controls. Using the DOPA and 5-HTP accumulation as an estimate for the rate of tyrosine and tryptophan hydroxylase activity, respectively, the present results demonstrate: (1) an increased demand on catecholamine synthesis in the neocortex, the amygdala and in the septal area; and (2) an increased dopamine and serotonin synthesis in the ventral striatum (excluding the olfactory tubercle), and in the dorsal striatum.
- Published
- 1991
87. The putative 5-HT1B receptor agonist CP-93,129 suppresses rat hippocampal 5-HT release in vivo: comparison with RU 24969
- Author
-
Rui Tao and Stephan Hjorth
- Subjects
Agonist ,Male ,medicine.medical_specialty ,Microdialysis ,Serotonin ,Indoles ,medicine.drug_class ,Pyridines ,Methiothepin ,Citalopram ,Pharmacology ,Hippocampus ,Reuptake ,In vivo ,Internal medicine ,medicine ,Animals ,Pyrroles ,Receptor ,5-HT receptor ,Brain Chemistry ,Chemistry ,Rats, Inbred Strains ,Ligand (biochemistry) ,Rats ,Endocrinology ,Receptors, Serotonin ,Dialysis ,medicine.drug - Abstract
We have compared the ability of the new putatively specific 5-HT1B receptor agonist CP-93,129 (3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b] pyrid-5-one) and the structurally related mixed 5-HT1A/5-HT1B receptor ligand RU 24969, to influence 5-HT release in brain in vivo, using microdialysis techniques in chloral hydrate-anaesthetised rats. CP-93,129 (3 or 10 microM, via the dialysis perfusion medium) caused a concentration-dependent and methiothepin (10 microM)-sensitive suppression of ventral hippocampal 5-HT output. The effect of RU 24969 on 5-HT output was dependent on whether or not the 5-HT reuptake blocker citalopram was present in the perfusion medium. Thus, RU 24969 (0.1 microM) induced a decrease, or an increase followed by a decrease (1 microM), in 5-HT output in the absence of citalopram, but monotonically decreased (1 microM) 5-HT release when citalopram (1 microM) was present. CP-93,129 decreased dialysate 5-HT in either condition. Our findings are consistent with the characterisation of CP-93,129 as a 5-HT1B receptor agonist, and may thus represent in vivo support for 5-HT1B autoreceptor-mediated feedback control of 5-HT release in the rat brain. The 5-HT1B selectivity of CP-93,129, and its lack of 5-HT reuptake blocking properties, suggests that the compound compares favourably with other purported 5-HT1B receptor agonists.
- Published
- 1991
88. Effect of the 5-HT1A receptor agonist 8-OH-DPAT on the release of 5-HT in dorsal and median raphe-innervated rat brain regions as measured by in vivo microdialysis
- Author
-
Trevor Sharp and Stephan Hjorth
- Subjects
Male ,medicine.medical_specialty ,Microdialysis ,Serotonin ,Tetrahydronaphthalenes ,Hippocampus ,Nucleus accumbens ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Dorsal raphe nucleus ,Internal medicine ,medicine ,Animals ,General Pharmacology, Toxicology and Pharmaceutics ,8-Hydroxy-2-(di-n-propylamino)tetralin ,musculoskeletal, neural, and ocular physiology ,Brain ,Rats, Inbred Strains ,General Medicine ,Rats ,Perfusion ,Kinetics ,Endocrinology ,Globus pallidus ,nervous system ,Organ Specificity ,Receptors, Serotonin ,Autoreceptor ,5-HT1A receptor ,Raphe Nuclei ,Raphe nuclei ,Dialysis - Abstract
Recent electrophysiological studies, measurements of 5-HT synthesis and in vivo voltammetry recordings of 5-HT metabolism have suggested that serotoninergic neurones in the median raphe (MR) are less sensitive to 5-HT1A autoreceptor stimulation relative to those in the dorsal raphe (DR). To further study the putative differences in regulation between ascending 5-HT projections from the raphe nuclei we have used microdialysis to measure the release of 5-HT in ventral hippocampus, globus pallidus, dorsal hippocampus, frontal cortex, nucleus accumbens and medial septum, following systemic administration of the specific 5-HT1A agonist 8-OH-DPAT. The results show that the baseline output of 5-HT was similar in each of the areas studied. While 8-OH-DPAT decreased dialysate levels of 5-HT in all areas, the inhibition of 5-HT release seen in globus pallidus was significantly less marked compared to that observed in the other five regions. The results indicate that 5-HT1A autoreceptor-mediated control of 5-HT release is functional in all of the brain areas studied, including those receiving a preferential 5-HT innervation from the DR and MR. We find little evidence in support of the idea that brain 5-HT neuronal projections are heterogenous with respect to 5-HT1A autoreceptor regulation of 5-HT release; the globus pallidus, however representing a possible exception to this.
- Published
- 1991
89. Application of brain microdialysis to study the pharmacology of the 5-HT1A autoreceptor
- Author
-
Stephan Hjorth and Trevor Sharp
- Subjects
Agonist ,Microdialysis ,Serotonin ,medicine.drug_class ,Pharmacology ,Biology ,Inhibitory postsynaptic potential ,chemistry.chemical_compound ,Dorsal raphe nucleus ,polycyclic compounds ,medicine ,Animals ,Humans ,heterocyclic compounds ,5-HT receptor ,Brain Chemistry ,8-OH-DPAT ,musculoskeletal, neural, and ocular physiology ,General Neuroscience ,Microchemistry ,nervous system ,chemistry ,Receptors, Serotonin ,Autoreceptor ,Raphe nuclei ,Neuroscience ,Dialysis - Abstract
5-Hydroxytryptamine (5-HT) receptors of the 5-HT1A subtype are localized on serotoninergic cells and dendrites in the raphe nuclei of the brain stem and are believed to regulate synaptic 5-HT release through an inhibitory influence on serotoninergic impulse flow. The effects of 5-HT1A agonists on 5-HT release can, therefore, only be detected by measurement of 5-HT release from intact serotoninergic neurones. Here we review the evidence that the microdialysis technique, when applied to the anaesthetized rat, is able to detect extracellular 5-HT in the brain which derives from serotoninergic neurones and changes in accordance with serotoninergic neuronal activity. We have observed that a range of 5-HT1A agonists, including 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), inhibit 5-HT release in hippocampus, most probably by acting on somatodendritic 5-HT1A autoreceptors in the dorsal raphe nucleus. The inhibitory action of 8-OH-DPAT and several other selective 5-HT1A receptor active drugs on 5-HT release is sensitive to pindolol, further supporting the idea that the 5-HT receptor being measured is of the 5-HT1 subtype. Two drugs, BMY 7378 and NAN-190, which show 5-HT1A antagonist properties in certain models, reduce 5-HT release indicating that they have mixed agonist/antagonist actions at the 5-HT1A receptor. Our data indicate that measurement of 5-HT release in rat brain using the microdialysis technique may be a useful method to probe the pharmacology of the 5-HT1A autoreceptor in vivo.
- Published
- 1990
90. cis-(+)-8-OH-1-CH3-DPAT, (+)ALK-3, a novel stereoselective pharmacological probe for characterizing 5-HT release-controlling 5-HT1A autoreceptors. An in vivo brain microdialysis study
- Author
-
Stephan Hjorth, Ye Liu, and Trevor Sharp
- Subjects
Agonist ,Male ,Microdialysis ,Serotonin ,Tetrahydronaphthalenes ,medicine.drug_class ,Pharmacology ,Naphthalenes ,Partial agonist ,Hippocampus ,medicine ,Animals ,Receptor ,5-HT receptor ,Brain Chemistry ,8-Hydroxy-2-(di-n-propylamino)tetralin ,Chemistry ,Rats, Inbred Strains ,Stereoisomerism ,General Medicine ,Hydroxyindoleacetic Acid ,Rats ,nervous system ,Pindolol ,Receptors, Serotonin ,Autoreceptor ,5-HT1A receptor ,3,4-Dihydroxyphenylacetic Acid ,Dialysis ,Serotonin Agonist - Abstract
The somatodendritic 5-HT1A autoreceptor regulating 5-HT neuronal activity is currently poorly defined pharmacologically because there are no specific antagonists, but also because potent and stereoselective agonists are scarce. Moreover, there have been few, if any, attempts to specifically investigate structure-activity relationships for agonists acting at this site. Employing brain microdialysis techniques, we have examined the effects of the enantiomers of cis-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin (ALK-3; 0.01-0.3 mg/kg s.c.), its trans-1-methyl analogue (ALK-4; 0.3 mg/kg s.c.) and the pure enantiomers of the parent compound - 8-OH-DPAT (0.3 mg/kg s.c.) — in an attempt to address stereochemical agonist structure-activity requirements of 5-HT release-controlling 5-HT1A autoreceptors in brain. The cis-1-methylated 8-OH-DPAT analogue (+)ALK-3 was comparable to the parent compound in reducing the 5-HT output from rat ventral hippocampus. In comparison, both (−)ALK-3 and the racemic rans-diastereomer to ALK-3, ALK-4, were inactive, while the two stereoisomers of 8-OH-DPAT strongly reduced 5-HT release. Pretreatment with (−)pindolol (8 mg/kg s.c.), which has high affinity for 5-HT1A radioligand binding sites, blocked the reduction of hippocampal 5-HT release induced by a submaximally effective dose of (+)ALK-3. The direct intrahippocampal administration of (+)ALK3 (10 μM) via the perfusion medium did not affect 5-HT output. In summary, the data indicate that (+)ALK-3, like 8-OH-DPAT, is a very potent 5-HT receptor agonist which inhibits terminal 5-HT release in rat hippocampus, probably via activation of somatodendritic 5-HT1A autoreceptors. However, unlike 8-OH-DPAT, (+)ALK-3 is highly stereoselective and may therefore represent a useful probe in the further characterization of 5-HT1A receptor-mediated mechanisms and function. The present study defines some of the stereochemical requirements for 5-HT1A receptor interaction, emphasizing the importance of the receptor region complementary to the C1 and C2 carbons of the 8-OH-DPAT molecule. These findings contribute to the establishment of structure-activity relationships for the cell body 5-HT1A autoreceptors and might be of value in resolving structural features that determine agonist/antagonist activity at central 5-HT1A receptors. Finally, in conjunction with our recent finding that (+)ALK-3 is a partial agonist at postsynaptic 5HT1A receptors, the present study extends previous observations suggesting that pre- and postsynaptic 5-HT1A receptor populations differ in their characteristics.
- Published
- 1990
91. Implantable microencapsulated dopamine (DA): prolonged functional release of DA in denervated striatal tissue
- Author
-
A. McRae, Stephan Hjorth, David W. Mason, Lynn Dillon, and Thomas R. Tice
- Subjects
Functional observations ,medicine.anatomical_structure ,Dopamine ,In vivo ,Prolonged release ,Chemistry ,Central nervous system ,Drug delivery ,medicine ,Excipient ,Pharmacology ,Biocompatible material ,medicine.drug - Abstract
Biodegradable controlled-release microcapsule systems made with the biocompatible biodegradable polyester excipient poly [DL-lactide-co-gly-colide] constitute an exciting new technology for drug delivery to the central nervous system (CNS). The present study describes functional observations indicating that implantation of dopamine (DA) microcapsules encapsulated within two different polymer excipients into denervated striatal tissue assures a prolonged release of the transmitter in vivo. This technology has a considerable potential for basic and possibly clinical research.
- Published
- 1990
92. Introduction — Neuroregulation of serotoninergic systems: basic and clinical perspectives
- Author
-
Stephan Hjorth and Peter H. Hutson
- Subjects
Pharmacology ,Psychiatry and Mental health ,business.industry ,Neuroregulation ,Medicine ,Pharmacology (medical) ,business ,Serotonergic ,Neuroscience - Published
- 2000
93. P.1.173 In vivo studies on the brain serotonin output in experimental chronic hepatic encephalopathy
- Author
-
Finn Bengtsson, Cecilia Wikell, Peter B. F. Bergqvist, Stephan Hjorth, and Gustav Apelqvist
- Subjects
Pharmacology ,Psychiatry and Mental health ,Neurology ,business.industry ,In vivo ,Chronic hepatic encephalopathy ,Medicine ,Pharmacology (medical) ,Neurology (clinical) ,Serotonin ,business ,Biological Psychiatry - Published
- 1997
94. P.1.016 Effects of a single venlafaxine challenge on the neocortical monoamine output in experimental chronic hepatic encephalopathy
- Author
-
Cecilia Wikell, Peter B. F. Bergqvist, Finn Bengtsson, Gustav Apelqvist, and Stephan Hjorth
- Subjects
Pharmacology ,medicine.medical_specialty ,business.industry ,Venlafaxine ,Psychiatry and Mental health ,Endocrinology ,Monoamine neurotransmitter ,Neurology ,Internal medicine ,Chronic hepatic encephalopathy ,Medicine ,Pharmacology (medical) ,Neurology (clinical) ,business ,Biological Psychiatry ,medicine.drug - Published
- 1997
95. Potassium-evoked neuronal release of serotonin in experimental chronic hepatic encephalopathy
- Author
-
Finn Bengtsson, Gustav Apelqvist, Stephan Hjorth, and Peter B. F. Bergqvist
- Subjects
medicine.medical_specialty ,Endocrinology ,chemistry ,business.industry ,Internal medicine ,Potassium ,Chronic hepatic encephalopathy ,Medicine ,chemistry.chemical_element ,Serotonin ,business ,Biological Psychiatry - Published
- 1997
96. Citalopram and release of brain 5-HT in experimental chronic hepatic encephalopathy
- Author
-
Gustav Apelqvist, Stephan Hjorth, Finn Bengtsson, Cecilia Wikell, and Peter B. F. Bergqvist
- Subjects
business.industry ,Chronic hepatic encephalopathy ,Medicine ,Pharmacology ,Citalopram ,business ,Biological Psychiatry ,5-HT receptor ,medicine.drug - Published
- 1997
97. P-chloroamphetamine- and D-fenfluramine-induced brain 5-HT release in chronic hepatic encephalopathy
- Author
-
Finn Bengtsson, Peter B. F. Bergqvist, Gustav Apelqvist, Cecilia Wikell, and Stephan Hjorth
- Subjects
medicine.medical_specialty ,Endocrinology ,Fenfluramine ,business.industry ,Internal medicine ,medicine ,Chronic hepatic encephalopathy ,business ,P-Chloroamphetamine ,Biological Psychiatry ,5-HT receptor ,medicine.drug - Published
- 1997
98. Is 3-PPP a potential antipsychotic agent? Evidence from animal behavioural studies
- Author
-
Domingo Sanchez, Stephan Hjorth, David Clark, Jörgen A. Engel, Kjell Svensson, and Arvid Carlsson
- Subjects
Male ,Agonist ,Dextroamphetamine ,Time Factors ,medicine.drug_class ,medicine.medical_treatment ,Motor Activity ,Pharmacology ,Antipsychotic Agent ,Piperidines ,Dopamine ,Dopamine receptor D2 ,Avoidance Learning ,medicine ,Animals ,Humans ,Antipsychotic ,Behavior, Animal ,Rats, Inbred Strains ,Rats ,Stereotypy (non-human) ,Autoreceptor ,Stereotyped Behavior ,Psychology ,Neuroscience ,Antipsychotic Agents ,medicine.drug - Abstract
The action of the dopamine autoreceptor agonist 3-PPP was examined in several putative models of antipsychotic action. Whereas this agent was capable of reducing d-amphetamine-induced locomotor stimulation at low doses, it was strikingly less potent in modifying conditioned avoidance responding and d-amphetamine-induced stereotypy. These findings are discussed in relation to a preferential action of 3-PPP on limbic dopamine mechanisms, and to the drug's potential as an antipsychotic agent devoid of extrapyramidal side-effects.
- Published
- 1982
99. Anxiolytic-like action of the 3-PPP enantiomers in the Vogel conflict paradigm
- Author
-
Arvid Carlsson, Jörgen A. Engel, and Stephan Hjorth
- Subjects
Male ,Agonist ,medicine.drug_class ,Drinking ,Neurotransmission ,Pharmacology ,Receptors, Dopamine ,Anxiolytic like ,Conflict, Psychological ,Piperidines ,Dopamine ,Avoidance Learning ,medicine ,Animals ,Receptor ,Dose-Response Relationship, Drug ,Rats, Inbred Strains ,Stereoisomerism ,Rats ,Apomorphine ,Anxiety ,medicine.symptom ,Enantiomer ,Arousal ,Psychology ,medicine.drug - Abstract
The effect of the (+)- and (-)-enantiomers of 3-PPP [conventional and atypical dopamine (DA)-receptor active agent, respectively] were investigated in a commonly used animal model of anxiety: the Vogel licking-conflict test. Low doses (≤0.5 mg/kg SC) of both 3-PPP enantiomers resulted in anti-conflict (=anxiolytic-like) actions in this test. (-)-3-PPP proved to be almost as potent as apomorphine in releasing the punished responding (minimum effective doses; (-)-3-PPP: 0.016, and apomorphine: 0.006 mg/kg SC), whereas (+)-3-PPP was about 10 times less effective than apomorphine. In the higher dose range (≥1.0 mg/kg), both 3-PPP enantiomers instead induced an apparent “pro”-conflict effect; i.e. decreased responding to a level significantly below baseline, thus resulting in a biphasic dose-response curve. Simple alterations in the animals' motivation to drink, in shock threshold or in motor capabilities did not seem to be major explanatory factors either for the anti- or for the “pro”-conflict effects. With regard to the latter, the possibility is discussed of an interaction between the experimental test situation and non conflict-related effects of the drugs, thus interfering with the punished drinking. The findings are interpreted within the concept that low doses of the 3-PPP enantiomers, in particular (-)-3-PPP, may attenuate anxiety-elicited increases in the neurotransmission in certain meso-cortical/limbic DA pathways, i.e. consistent with the previously shown preferentially “limbic” net antidopaminergic profile of action of (-)-3-PPP. The results support an active role for DA in conditions associated with anxiety and reinforce the view that novel putative anxiolytics might be found among selective DA-modulating agents like, e.g. the atypical DA receptor agonist (-)-3-PPP.
- Published
- 1987
100. Buspirone: Effects on central monoaminergic transmission - possible relevance to animal experimental and clinical findings
- Author
-
Stephan Hjorth and Arvid Carlsson
- Subjects
Male ,medicine.medical_treatment ,Pharmacology ,Neurotransmission ,Synaptic Transmission ,Receptors, Dopamine ,Buspirone ,Dopamine ,Monoaminergic ,Animals ,Medicine ,Receptor ,Adrenergic alpha-Antagonists ,Behavior, Animal ,business.industry ,Brain ,Rats, Inbred Strains ,Receptors, Adrenergic, alpha ,Rats ,Stimulant ,Pyrimidines ,Monoamine neurotransmitter ,Receptors, Serotonin ,Antidepressant ,business ,medicine.drug - Abstract
The weak neuroleptic agent buspirone, reported to possess ‘anxioselective’ and antidepressant actions in man, has pronounced effects on brain monoamine neurotransmission. Thus it is demonstrated that, apart from its dopamine antagonistic action, buspirone acts as a stimulant and a blocker of central 5-HT and α-adrenergic receptors, respectively. The relevance of these findings for the compound's clinical activity are discussed.
- Published
- 1982
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.