piperidines and 1-(3-chlorophenyl)piperazine

A rapidly growing body of data suggests that dysfunction in serotonergic (5-HT) function may be involved in the pathophysiology of schizophrenia, and that pharmacologic agents for this illness have their therapeutic effects mediated through serotonergic mechanisms. The purpose of this paper is to critically review data relevant to 5-HT's role in the pathophysiology and drug treatment of schizophrenia. Pathophysiologic evidence includes the psychotomimetic effects of lysergic acid (LSD), postmortem studies, single-dose 'challenge' studies and investigations of CSF and peripheral levels of 5-HT and its metabolites. The current nomenclature, potential therapeutic effects and importance of 5-HT receptor subtype antagonism will be examined. In addition, relatively novel strategies of 5-HT uptake blockade and direct acting 5-HT agonists will be assessed. A hypothesis of cortical-subcortical imbalance with an increase in subcortical 5-HT function responsible for positive symptoms and a decrease in prefrontal 5-HT function responsible for negative symptoms is proposed. Future implications of these data are discussed.

Topics: Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Humans; Isoxazoles; Piperazines; Piperidines; Risperidone; Schizophrenia; Serotonin; Tryptophan

Serotonin 5-HT2B receptor antagonists have been proposed as migraine prophylactic drugs, but previously available 5-HT2B receptor antagonists displayed multiple monoaminergic side effects and had to be withdrawn from the market. Here, we set out to identify a novel antagonist with high affinity and selectivity towards 5-HT2B receptors. To test the affinity of new compounds towards various receptors, we generated a broad series of cells functionally coupling human monoaminergic receptors to luciferase. Using the cell lines we revealed pimethixene (1-methyl-4-(9H-thioxanthen-9-ylidene)piperidine) as highly potent, albeit non-selective 5-HT2B receptor antagonist and optimized its chemical structure to create highly potent and selective 5-HT2B receptor antagonists. We selected the methoxythioxanthene BF-1 for further analysis. In comparison to pimethixene, it lacked high affinities to 5-HT1A, 5-HT2A, 5-HT2C, histamine H1, dopamine D1 and D2 as well as muscarinic M1 and M2 receptors. BF-1 was tested as potential migraine prophylactic drug by blocking meta-chlorophenylpiperazine, (mCPP) or BW723C86 (5-((thiophen-2-yl)methoxy)-α-methyltryptamine) induced neurogenic dural plasma protein extravasation in a guinea pig model that may resemble a migraine attack. BF-1 was significantly more potent in this assay compared to the well know non-selective 5-HT2B antagonists, methysergide ((6aR,9R)-N-[(2S)-1-Hydroxybutan-2-yl]-4,7-dimethyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide) or pizotifen (4-(1-methyl-4-piperidylidine)-9,10-dihydro-4H-benzo-[4,5]cyclohepta[1,2]-thiophene). Therefore, we propose BF-1 as a new compound that may be developed for prophylactic migraine treatment without the typical monoaminergic side effects.

Topics: Animals; Blood Proteins; Brain; Cell Line; Guinea Pigs; Humans; Indoles; Male; Piperazines; Piperidines; Receptor, Serotonin, 5-HT2B; Serotonin 5-HT2 Receptor Antagonists; Substrate Specificity; Thiophenes; Thioxanthenes; Xanthenes

Glucagon-like peptide-1 (GLP-1), an incretin hormone, is released from intestinal L cells in response to nutrient ingestion. Dipeptidyl peptidase-4 (DPP-4) rapidly degrades the active form of GLP-1 to an inactive form in the bloodstream. The present study aimed to investigate the role of serotonin (5-HT)1B receptors in the regulation of plasma active GLP-1 levels and glucose tolerance under DPP-4 inhibition.. C57BL6J mice treated with or without alogliptin, a highly selective DPP-4 inhibitor, for 4 days were intraperitoneally injected with either saline, the 5-HT1B/2C receptor agonist meta-chlorophenylpiperazine (mCPP) at 2.5mg/kg and 5mg/kg or the selective 5-HT1B receptor agonist CP94253 at 2.5mg/kg and 5mg/kg, and food-deprived after treatment. An hour later, plasma active GLP-1 levels were determined. Also, a glucose tolerance test was done by injecting D-glucose (2g/kg) following the injection of saline or CP94253 (5mg/kg) in mice treated with alogliptin.. Intraperitoneal injection of mCPP (2.5 and 5mg/kg) or CP94253 (2.5 and 5mg/kg) in mice treated with alogliptin for 4 days significantly increased plasma active GLP-1 levels compared with saline controls in mice that were food-deprived after the injections. While intraperitoneal injection of either mCPP or CP94253 alone had no significant effect on plasma active GLP-1 levels, the injection of CP94253 improved glucose tolerance in mice treated with alogliptin compared with saline.. These findings suggest that pharmacological stimulation of 5-HT1B receptors enhances the increases in plasma active GLP-1 induced by DPP-4 inhibition independently of feeding and also improves glucose tolerance in mice.

Topics: Administration, Oral; Animals; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Therapy, Combination; Food-Drug Interactions; Glucagon-Like Peptide 1; Glucose Intolerance; Injections, Intraperitoneal; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Mice, Inbred C57BL; Piperazines; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1B; Serotonin 5-HT1 Receptor Agonists; Up-Regulation; Uracil

Previous research indicates that serotonin enhances the development of stress-induced changes in behavior, although it is unclear which serotonin receptors mediate this effect. 5-HT2 receptors are potential candidates because activation at these receptors is associated with increased fear and anxiety. In this study, we investigated whether pharmacological treatments targeting 5-HT2 receptors would alter the acquisition and expression of conditioned defeat. Conditioned defeat is a social defeat model in Syrian hamsters in which individuals display increased submissive and defensive behavior and a loss of territorial aggression when tested with a novel intruder 24 hours after an acute social defeat. The nonselective 5-HT2 receptor agonist mCPP (0.0, 0.3, 1.0, or 3.0 mg/kg) was injected either prior to social defeat training or prior to conditioned defeat testing. Also, the 5-HT2A receptor antagonist MDL 11,939 (0.0, 0.5, or 2.0 mg/kg) was injected either prior to social defeat training or prior to conditioned defeat testing. Injection of mCPP prior to testing increased the expression of conditioned defeat, but injection of mCPP prior to training did not alter the acquisition of conditioned defeat. Conversely, injection of MDL 11,939 prior to training reduced the acquisition of conditioned defeat, but injection of MDL 11,939 prior to testing did not alter the expression of conditioned defeat. Our data suggest that mCPP activates 5-HT2C receptors during testing to enhance the display of submissive and defensive behavior, whereas MDL 11,939 blocks 5-HT2A receptors during social defeat to disrupt the development of the conditioned defeat response. In sum, these results suggest that serotonin acts at separate 5-HT2 receptors to facilitate the acquisition and expression of defeat-induced changes in social behavior.

Topics: Analysis of Variance; Animals; Conditioning, Psychological; Cricetinae; Disease Models, Animal; Dominance-Subordination; Male; Mesocricetus; Piperazines; Piperidines; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Serotonin Antagonists; Serotonin Receptor Agonists; Stress, Psychological

The mechanisms underlying individual differences in the response to serotonergic drugs are poorly understood. Rat studies may contribute to our knowledge of the neuronal substrates that underlie these individual differences.. A pharmacobehavioural study was performed to assess individual differences in the sensitivity to serotonergic drugs in rats that were selected based on their response to a novel environment.. Low responders (LR) and high responders (HR) to novelty rats were tested on the elevated T-maze following systemic injections of increasing doses of various serotonergic agents. The duration of avoidance of the open arms was scored for five trials.. The duration of avoidance behaviour was larger in saline-treated LR rats compared to saline-treated HR rats. The 5-HT1A agonist 8-OH-DPAT and the 5-HT2 agonists mCPP and DOI decreased the duration of avoidance behaviour in LR rats, but increased it in HR rats. The 5-HT3 agonist SR57227A and the 5-HT releaser/reuptake inhibitor d-fenfluramine increased the duration of avoidance behaviour in both types of rat. However, higher doses of SR57227A were required to alter avoidance behaviour in HR than in LR rats. The onset of the effects of SR57227A, d-fenfluramine and WAY100635 was faster in LR than in HR rats. The described effects were receptor specific. A model explaining the data is presented.. These data demonstrate that LR and HR rats differ in their sensitivity to serotonergic drugs that act at 5-HT3, 5-HT2 and 5-HT1A receptors. The implications of these individual differences for individual-specific treatment of substance abuse are briefly discussed.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Amphetamines; Animals; Avoidance Learning; Dose-Response Relationship, Drug; Exploratory Behavior; Fenfluramine; Individuality; Male; Maze Learning; Piperazines; Piperidines; Pyridines; Rats; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Serotonin Receptor Agonists

The cannabinoid and serotonin systems modulate feeding behavior in humans and laboratory animals. The present study assessed whether a cannabinoid (CB)(1) receptor antagonist and a serotonin (5-HT)(2C) receptor agonist alone and in combination attenuate motivation for the liquid nutritional drink Ensure as measured by a progressive ratio (PR) schedule of reinforcement in male C57BL/6 mice. Pretreatment (15 min i.p.) with either the CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716) (SR; Rimonabant or Acomplia) or the 5-HT(2C) receptor agonist m-chlorophenylpiperazine (mCPP) dose-dependently decreased the maximum ratio completed under the PR schedule (break point) in mice. ED(25) values for SR and mCPP to decrease break point were determined, and the relative potency of each drug alone was quantified. Fixed dose-ratio pairs of SR/mCPP based on their relative potency were then administered. Dose-addition analysis comparing the experimentally determined potency for SR/mCPP combinations with their predicted additive potency revealed that SR/mCPP combinations in 1:1 and 2:1 ratios based on relative potency produced significant synergistic attenuation of break point for Ensure. The ED(25) values for decreasing break point were consistently lower than ED(25) values for decreasing response rate, and synergistic effects of SR/mCPP combinations on break point were seen independent of synergistic effects on response rate. These results indicate that cannabinoid CB(1) and serotonin 5-HT(2C) receptors are involved in motivated feeding behavior in mice and that these compounds can synergistically modulate motivation for palatable food with the synergy dependent upon the ratio of SR/mCPP in the combination.

Topics: Animals; Drug Synergism; Feeding Behavior; Male; Mice; Piperazines; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Serotonin, 5-HT2C; Rimonabant; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists

This study introduces a laboratory model of compulsive behavior based on persistence in the context of rewarded spatial alternation.. Rats were screened for spontaneous persistence during T-maze reinforced alternation. Experiment 1: One high and one low spontaneous persistence group (n = 8) received 20 injections of fluoxetine, a matched pair saline, both followed by 4 days of meta-chlorophenylpiperazine (mCPP) challenge. Experiment 2: Five matched groups of rats (n = 9) received pretreatment (20 injections) with fluoxetine, mCPP, desipramine, diazepam or saline, followed by 4 days of mCPP challenge (fluoxetine in mCPP group). After washout, animals received 2 days of naratriptan, followed by another 2-day mCPP challenge.. In both experiments mCPP significantly increased persistence in saline controls. Fluoxetine also acutely increased persistence scores: after a gradual return to baseline, these scores showed tolerance to mCPP. Experiment 1: This pattern was significant in high but not low initial persistence groups. Experiment 2: Fluoxetine and mCPP showed cross-tolerance. Neither desipramine nor diazepam protected against mCPP challenge. Persistence scores returned to baseline during washout and naratriptan and were thereafter increased by another mCPP challenge in all but the fluoxetine and mCPP groups, suggesting 5-HT2C receptor mediation.. This model is based on spontaneous persistence behavior showing pharmacological responses concordant with those of compulsive symptomatology.

Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents, Tricyclic; Desipramine; Diazepam; Disease Models, Animal; Fluoxetine; Indoles; Male; Maze Learning; Obsessive-Compulsive Disorder; Piperazines; Piperidines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1D; Receptor, Serotonin, 5-HT2C; Reinforcement, Psychology; Selective Serotonin Reuptake Inhibitors; Serotonin Receptor Agonists; Tryptamines

Direct-acting serotonin (5-HT) receptor agonists increase serum corticosterone in rats by activating receptors of the 5-HT(1A) or the 5-HT(2A/2C) subtypes. While involvement of 5-HT(1A) receptors in activation of the hypothalamic-pituitary-adrenocortical (HPA) axis is clear, the 5-HT(2) receptor subtype--5-HT(2A) or 5-HT(2C)--responsible for activation of the HPA axis by direct-acting 5-HT(2) receptor agonists has been difficult to determine due to the lack of selective pharmacologic agents. Recently, however, 5-HT(2) receptor antagonists with high selectivity for 5-HT(2A) and 5-HT(2C) receptor subtypes have been discovered. The selective 5-HT(2A) receptor antagonist MDL 100,907 and the selective 5-HT(2C) receptor antagonist SB 242084 were used to block the increases in rat serum corticosterone elicited by 5-HT(2) receptor agonists with varying degrees of affinity for 5-HT(2A) and 5-HT(2C) receptors. MDL 100,907 was fully effective in blocking the increases in corticosterone concentrations produced by quipazine, DOI, m-CPP and Ro 60-0175, whereas SB 242084 was ineffective or was only marginally effective. Our findings implicate 5-HT(2A) receptors rather than 5-HT(2C) receptors in mediating increases in rat serum corticosterone produced by direct-acting 5-HT(2) receptor agonists in vivo.

Topics: Aminopyridines; Amphetamines; Animals; Corticosterone; Dose-Response Relationship, Drug; Ethylamines; Fluorobenzenes; Hypothalamo-Hypophyseal System; Indoles; Male; Piperazines; Piperidines; Quipazine; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists

The ability of m-CPP [1-(m-chlorophenyl)piperazine] to produce hypolocomotion is well documented. This effect has been postulated to be due to activation of the 5-HT(2C) receptor. It is only recently that the tools necessary to clearly delineate which serotonin receptors are involved in the mediation of m-CPP hypolocomotion have become available. We investigated the effects of the selective 5-HT(2A) antagonists, MDL 100,907 and ketanserin, the selective 5-HT(2B) antagonists, LY 202146 and LY 266097, the 5-HT(2B/2C) antagonist, SB 206553, and the selective 5-HT(2C) antagonist, SB 242084 on m-CPP-induced hypolocomotion and spontaneous locomotor activity in mice. Furthermore, we investigated the effects of the non-selective serotonin antagonists, ritanserin, LY 53857, mianserin and cyproheptadine on m-CPP hypolocomotion. Additionally, receptor-binding studies were employed as an in vitro assessment of relative affinities at the 5-HT(2A), 5-HT92B) and 5-HT(2C) receptors. Antagonists tested alone were without effect on spontaneous activity, with the sole exception of ketanserin, which decreased spontaneous activity at the high dose of 1 mg/kg. m-CPP-induced hypolocomotion was not significantly attenuated by various doses of MDL 100,907, ketanserin, LY 202146, LY 266097, ritanserin or cyproheptadine. In contrast, SB 206553, SB 242084, LY 53857 and mianserin were capable of reversing m-CPP-induced hypolocomotion. Consistent with previous suggestions, a detailed pharmacological evaluation with selective antagonists for the 5-HT2 family of receptors supports a primary role for the 5-HT(2C) receptor, and not 5-HT(2A) or 5-HT(2B) receptors, in mediating the hypolocomotion produced by m-CPP.

Topics: Amphetamines; Animals; Binding, Competitive; Cell Line; Cricetinae; Fluorobenzenes; Humans; Kinetics; Male; Mice; Mice, Inbred Strains; Motor Activity; Piperazines; Piperidines; Radioligand Assay; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2B; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Serotonin Agents; Serotonin Antagonists

Employing a Fixed-Ratio 10, food-reinforced protocol, rats were trained to recognize the discriminative stimulus (DS) properties of the novel, potent, 5-HT2C agonist, Ro 60-0175 (2.5 mg/kg, i.p.). This schedule generated appropriate drug versus vehicle responding after 50 + 5 training sessions and Ro 60-0175 elicited full (100%) drug selection with an effective dose50 (ED50) of 0.6 mg/kg, i.p.. The 5-HT2C receptor agonists, mCPP and MK 212, fully generalized to Ro 60-0175 with ED50s of 0.8 and 0.4 mg/kg, s.c., respectively, whereas the preferential 5-HT2B agonist, BW 723C86 ( > 10.0 mg/kg, s.c.) and the 5-HT2A agonist, DOI ( > 2.5 mg/kg, s.c.), were ineffective. The 5-HT2A/2B/2C receptor antagonist, mianserin, dose-dependently blocked the DS properties of Ro 60-0175 with an ED50 of 0.7 mg/kg, s.c. This action was mimicked by the novel, 5-HT2B/2C antagonist, SB 206,553 (ED50 = 0.3 mg/kg, s.c.), whereas the selective 5-HT2A antagonist, MDL 100,907 ( > 0.63 mg/kg, s.c.), was ineffective. Further, the selective 5-HT2C antagonist, SB 242,084, dose-dependently and fully blocked drug selection (ED50 = 0.2 mg/kg, i.p.), whereas the selective 5-HT2B antagonist, SB 204,741, was not active ( > 0.63 mg/kg, i.p.). In conclusion, these data demonstrate that Ro 60-0175 generates a robust DS and suggest that activation of 5-HT2C receptors is the principal mechanism underlying its DS properties.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Aminopyridines; Animals; Conditioning, Operant; Ethylamines; Fluorobenzenes; Indoles; Male; Mianserin; Piperazines; Piperidines; Pyrazines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Reinforcement, Psychology; Serotonin Antagonists; Serotonin Receptor Agonists; Thiophenes

We have recently demonstrated that a single administration of m-chlorophenylpiperazine (m-CPP, a preferential 5-HT2C receptor agonist) produces tolerance to its stimulatory effect on adrenocorticotropic hormone (ACTH) concentrations when challenged 24 h later with the same dose of m-CPP. In the present study, we studied the effects of pretreatment with various N-methyl-D-aspartate (NMDA) receptor antagonists on development of tolerance to m-CPP's stimulatory effect on ACTH concentrations. Pretreatment with various NMDA receptor antagonists such as 5.7-dichlorokynurenic acid (1.0 mg/kg), 3-amino-1-hydroxy 2-pyrrolidone (1.0 mg/kg), dizocilpine (0.1 mg/kg) and ifenprodil (1.0 mg/kg) injected 30 min before the first injection of m-CPP (2.5 mg/kg) blocked development of tolerance to m-CPP's stimulatory effect on ACTH concentrations in rats injected 24 h later with the same dose (2.5 mg/kg) of m-CPP. These findings suggest that tolerance to postsynaptic 5-HT2C receptor-mediated response is initiated though stimulation of NMDA receptor complex and, furthermore, demonstrate a functional interaction between the 5-HT and glutamate systems.

Topics: Adrenocorticotropic Hormone; Animals; Dimethyl Sulfoxide; Dizocilpine Maleate; Drug Tolerance; Kynurenic Acid; Male; Phencyclidine; Piperazines; Piperidines; Pyrrolidinones; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Serotonin Receptor Agonists

The effect of the atypical neuroleptic zotepine (CAS 26615-21-4), in comparison with clozapine, risperidone and haloperidol, on the responsiveness of different 5-hydroxytryptamine (5-HT1) receptor subtypes to their agonists was examined in rats and mice. The above antipsychotics were investigated in the following behavioural tests: 8-OH-DPAT (8-hydroxy-dipropylaminotetralin)-induced behavioural syndrome in rats, mCPP (mchlorophenylpiperazine)-induced hypothermia in mice and mCPP-induced hypoactivity measured in the open field in rats. Zotepine, clozapine and haloperidol did not affect the behavioural syndrome induced by 8-OH-DPAT (the selective agonist of 5-HT1A, receptor), only risperidone (used in higher doses) attenuated the effect of 8-OH-DPAT. The mCPP-induced hypothermia in mice (a 5-HT1B effect) was affected by neither zotepine nor clozapine, risperidone and haloperidol, all of them used in low doses which did not influence per se the body temperature of mice. All the tested antipsychotics given at high doses induced hypothermia in control mice; at the same time, zotepine, clozapine and risperidone attenuated the hypothermic effect of mCPP. mCPP decreases the exploratory activity of rats, this effect being considered to be mediated by 5-HT1C receptors. The tested antipsychotics, used in low doses, influenced neither the exploratory activity nor the hypoactivity induced by mCPP. When used at higher doses, they induced hypoactivity in control rats; the hypoactivity after joint administration of zotepine, risperidone or haloperidol and mCPP was significantly greater than after mCPP alone, whereas clozapine slightly attenuated the effect of mCPP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Antipsychotic Agents; Behavior, Animal; Body Temperature; Clozapine; Dibenzothiepins; Exploratory Behavior; Haloperidol; Isoxazoles; Male; Mice; Motor Activity; Piperazines; Piperidines; Rats; Rats, Wistar; Receptors, Serotonin; Risperidone; Serotonin Antagonists; Serotonin Receptor Agonists

In this study, the elevated zero-maze model of anxiety was used to investigate CCK receptor antagonist effects on the behaviour of male Lister-hooded rats and to demonstrate, by administering antagonists in the presence or absence of selective 5-hydroxytryptamine (5-HT) re-uptake inhibitors, the involvement of 5-HT in the mediation of these effects. Devazepide, a selective CCKA receptor antagonist, L-365,260 (3R(+)-N-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin- 3-yl-N1- (3-methyl-phenyl)urea) or CI-988 (4-([2-[[3-(1H-indol-3-yl)-2-methyl-1- oxo-2-[[(tricyclo[3.3.1.1.(3.7)]-dec-2-yloxy)-carbonyl]-amin o]- propyl]-amino]-1-phenylethyl]-amino)-4-oxo-[R-(R*,R*)]-butanoate- N-methyl-D-glucamine), both selective CCKB receptor antagonists, were administered 30 min prior to testing. Behavioural analysis during testing included measures of risk-assessment behaviours (e.g. stretched-attend posture) in addition to time spent on the open quadrants. Devazepide induced significant anxiolytic effects, whereas CI-988 produced inconsistent results and L-365,260 was ineffective. When administered simultaneously with the 5-HT re-uptake inhibitors zimelidine or Wy 27587 (N-[[[1-[(6- fluoro-2-naphthalenyl)methyl]-4-piperidinyl]amino] carbonyl]-3-pyridine carboxamide methyl sulphonate salt), the significant anxiolytic effect induced by devazepide was dose-dependently and significantly attenuated. Zimelidine and Wy27587 had little effect alone on zero-maze behaviour at the lower of two doses given. These data show that the elevated zero-maze, in conjunction with the analysis of 'risk-assessment' behaviours, is an anxiety model which is sensitive to the anxiolytic effects of CCK receptor antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Anxiety Agents; Benzodiazepinones; Devazepide; Diazepam; Indoles; Male; Maze Learning; Meglumine; Niacinamide; Phenylurea Compounds; Piperazines; Piperidines; Rats; Receptors, Cholecystokinin; Selective Serotonin Reuptake Inhibitors; Zimeldine

The involvement of serotonin (5-HT) in oxytocin secretion was investigated in this study. Pharmacologic agents that influence serotonergic transmission were administered to conscious unrestrained male rats 30 min prior to sacrifice and plasma oxytocin concentration was measured by radioimmunoassay. The d- and l-stereoisomers of the 5-HT releaser fenfluramine significantly increased plasma oxytocin in a dose-dependent manner. Oxytocin secretion was more potently stimulated by d-fenfluramine than by l-fenfluramine. The 5-HT releaser p-chloroamphetamine also increased plasma oxytocin. The following 5-HT agonists increased plasma oxytocin concentration: the 5-HT1&2 agonist m-chlorophenyl-piperazine [10-20 mg/kg intraperitoneally (i.p.)], the 5-HT1C&2 agonist 1-(2,5-dimethoxy-4-l-phenyl)-2-aminopropane (0.5-2.0 mg/kg i.p.) and the 5-HT1&2 agonist 1-piperazinyl-6-chloropyrazine (10 mg/kg i.p.). In contrast, the 5-HT1AB agonist 5-methoxy-3-(1,2,3,4-tetrahydro-4-pyridinyl)-1H-indole (0.2-5.0 mg/kg i.p.) did not increase oxytocin secretion. Pretreatment with the 5-HT1C&2 antagonist, 6-(2-(4-[bis(4-fluorophenyl)methylene]-1-piperidinyl)ethyl)-7-methyl-5H- thiazolo(3(1)2-a)pyrimidin-5-one [2.5 mg/kg subcutaneously (s.c.)], 60 min before injection of 1-piperazinyl-6-chloropyrazine attenuated, but did not completely block, 1-piperazinyl-6-chloropyrazine-induced secretion of oxytocin. Both low and high (0.01 and 0.1 mg/kg s.c.) doses of 6-(2-(4-[bis(4-fluorophenyl)methylene]-1-piperidinyl)ethyl)-7-methyl-5H- thiazolo(3(1)2-a)pyrimidin-5-one or the 5-HT2 antagonist spiperone inhibited the 1-(2,5-dimethoxy-4-l-phenyl)-2-aminopropane-induced increases in plasma oxytocin. These studies provide evidence that enhanced serotonergic transmission stimulates oxytocin secretion and that 5-HT2 receptors contribute to this effect.

Topics: Animals; Male; Oxytocin; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Ritanserin; Serotonin; Synaptic Transmission

8-OH-DPAT (2.5-10 mg/kg) and buspirone (10 mg/kg) but not 5,7-DHT (200 micrograms/mouse), pCPA (75 and 150 mg/kg, three times), ritanserin (0.1 and 0.2 mg/kg), LY 53857 (1.5 and 3 mg/kg), GR 38032 F (0.1-100 micrograms/kg), TFMPP (5 and 20 mg/kg) and mCPP (2.5 and 5 mg/kg) antagonized the rise in body temperature that occurs to the last mice removed from their group housing, which was termed as stress-induced hyperthermia (SIH). Ro 15-1788, at a dose which blocked the effect of diazepam on SIH, did not reverse the anxiolytic effect of buspirione. Instead, when cerebral 5-HT content was reduced to 50% by 5,7-DHT-induced lesion, the effect of buspirone on SIH was decreased. TFMPP 5 mg/kg did not shorten significantly the onset of SIH as could have been expected by an anxiogenic drug, while the dose of 20 mg/kg did not modify the pattern of SIH at all. The lower dose of TFMPP evoked a hyperthermic and the higher a hypothermic response.

Topics: 5,7-Dihydroxytryptamine; 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Anti-Anxiety Agents; Body Temperature Regulation; Buspirone; Diazepam; Ergolines; Fenclonine; Fever; Flumazenil; Imidazoles; Male; Mice; Ondansetron; Piperazines; Piperidines; Ritanserin; Serotonin; Serotonin Antagonists; Stress, Psychological; Tetrahydronaphthalenes

The functional role of brain 5-HT and 5-HT receptor subtypes in periaqueductal gray (PAG) induced aversion has been investigated in rats. Antiaversive effects were found with the serotonin agonists TFMPP, mCPP and DOI but not with RU 24969 which was found to facilitate PAG aversion. The first three serotonin agonists share potent 5-HT1C activity while RU 24969 differs with a high 5-HT1A activity. Proaversive effects were found with the mixed 5-HT1C/5-HT2 antagonists cyproheptadine and ritanserin; this effect was already reported for the mixed 5-HT1C/5-HT2 antagonists metergoline and mianserin and is opposite to the effects of the selective 5-HT2 antagonists ketanserin, pirenperone, trazodone and spiperone. The antiaversive effects of mCPP (1 mg/kg) could be prevented by pretreatment of the animals with mianserin (1 and 10 mg/kg). These results suggest that 5-HT1C receptors play an important role in the serotonergic control of PAG aversion. 5-HT1C receptor activation seems to mediate antiaversive effects whereas acute 5-HT1C receptor blockade appears to facilitate PAG aversion. Functional interactions take place between several receptor types in the in vivo control of PAG aversion, where 5-HT1C receptors appear to play a predominant function.

Topics: Amphetamines; Animals; Cyproheptadine; Indoles; Ketanserin; Male; Periaqueductal Gray; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Reinforcement, Psychology; Ritanserin; Serotonin; Serotonin Antagonists

In pithed rats, m-chlorophenylpiperazine (m-CPP) produced marked, dose-dependent (ED50 = 0.18 mumol) increases in mean arterial blood pressure which peaked within 1 minute and were sustained over 15 minutes. Two serotonin antagonists, metergoline and ritanserin, completely blocked the pressor responses to 2.5 mg/kg m-CPP in pithed adrenal demedullated rats, while alpha-adrenergic blockade by prazosin plus yohimbine was without effect, suggesting that the doubling in blood pressure produced by m-CPP was mediated via serotonin receptors within blood vessels. Somewhat smaller increases in blood pressure over baseline values were observed after m-CPP administration to conscious, freely moving rats. A small but statistically significant increase in heart rate peaked 5 minutes after m-CPP and also was blocked by metergoline but was only minimally affected by ritanserin or the prazosin-yohimbine combination. These results with m-CPP support other evidence for two or more separable effects of serotonergic agonists on the peripheral cardiovascular system.

Topics: Adrenal Medulla; Animals; Blood Pressure; Brain; Heart Rate; Kinetics; Male; Metergoline; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Ritanserin; Serotonin Antagonists; Spinal Cord

The behavioral effects of the serotonin (5-HT) precursor l-5-hydroxytryptophan (l-5-HTP) and the phenylpiperazine 5-HT agonists 6-chloro-2-(1-piperazinyl)pyrazine (MK-212), 1-(m-trifluromethylphenyl) piperazine (TFMPP), 1-(m-chlorophenyl)piperazine (CPP) and 2-(1-piperazinyl)quinoline (quipazine) were compared with those of the putative 5-HT antagonists metergoline, methysergide, cyproheptadine, cinanserin and ketanserin under a multiple 5-min fixed-interval schedule of food or electric shock presentation in squirrel monkeys. Intramuscular administration of l-5-HTP (0.3-17 mg/kg), MK-212 (0.01-1.0 mg/kg), TFMPP and CPP (0.03-10 mg/kg) produced dose-related decreases in responding under both the food- and shock-presentation schedules. Quipazine differed from the other 5-HT agonists in that it increased shock-maintained behavior at doses (0.1-1.0 mg/kg) that decreased responding maintained by food. The 5-HT antagonists produced mixed behavioral effects. Metergoline (0.03-1.0 mg/kg), cyproheptadine (0.1-1.0 mg/kg) and cinanserin (1.0-10 mg/kg) produced dose-related increases in responding maintained by food, whereas only metergoline and methysergide increased behavior maintained by shock presentation. The prototype 5-HT2-receptor ligand ketanserin (0.3-10 mg/kg) differed from the other 5-HT antagonists in that it decreased behavior maintained by either event. Thus, performances maintained by food or shock presentation reveal both qualitative and quantitative differences in the behavioral effects of 5-HT receptor agonists and antagonists.

Topics: 5-Hydroxytryptophan; Animals; Cinanserin; Conditioning, Operant; Cyproheptadine; Electroshock; Female; Ketanserin; Male; Metergoline; Methysergide; Piperazines; Piperidines; Pyrazines; Quipazine; Receptors, Serotonin; Saimiri

1-Arylpiperazines (MK-212, quipazine, m-chlorophenylpiperazine and m-trifluoromethylphenylpiperazine) caused a serotonin (5-HT) receptor-mediated contraction of rat fundic strips. m-chlorophenylpiperazine and m-trifluoromethylphenylpiperazine had high affinity for the receptor but little efficacy, whereas quipazine and MK-212 had lesser affinity and much greater efficacy. 5-HT itself was the most potent (EC50 = 6-9 nM) agonist and possessed the greatest affinity (KA = 9.7 nM). Assessment of receptor occupancy vs. functional response (as well as receptor alkylation studies) demonstrated a very small, if any, receptor reserve in this tissue. Several arylquinolizines were found to be competitive antagonists of 5-HT-induced contraction, the most potent being L-653,267 and rauwolscine (KB values = 1.9 and 3.8 nM). Clozapine, trazodone and propranolol were identified as less potent, competitive antagonists, whereas various ergolines (including LY 53857), L-646,462 (cyproheptadine analog) and mianserin were noncompetitive. Potent 5-HT2 receptor antagonists (pirenpirone and ketanserin) antagonized only weakly or were without effect against 5-HT, indicating that the fundic 5-HT receptor is not of the 5-HT2 subtype. Because the fundic receptor has high affinity for 5-HT (as does the 5-HT1 binding site in brain tissue), the possible correspondence of the fundic 5-HT receptor with the 5-HT1 recognition site in rat brain cortex was considered. 5-HT, the nonindole agonists (1-arylpiperazines) and the competitive antagonists all competed with [3H]-5-HT for the 5-HT1 site. However, all compounds except 5-HT had Hill slopes significantly less than 1.0, precluding a valid comparison with dissociation constants derived pharmacologically in the fundus. With respect to having a high affinity for 5-HT, the 5-HT receptor mediating contraction of fundic smooth muscle resembles the 5-HT1 recognition site (as defined in brain tissue by radioligand binding), but identity remains unproven.

Topics: Animals; Binding, Competitive; Brain Chemistry; Gastric Fundus; In Vitro Techniques; Ketanserin; Male; Muscle Contraction; Piperazines; Piperidines; Propranolol; Pyrazines; Quipazine; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Tritium

5-HT uptake inhibitors and pirenperone (a 5-HT2 receptor antagonist), which in previous experiments antagonized fenfluramine (5-HT releaser)-induced hyperthermia in heat adapted rats, were tested against hyperthermia induced by the directly acting 5-HT agonist--m-CPP and quipazine. Pirenperone and --to a lesser degree--amitriptyline and femoxetine antagonized the hyperthermia. Citalopram and clomipramine were inactive. It is concluded that hyperthermia induced by 5-HT-like drugs in rats is due to the stimulation of the 5-HT2 receptor and that the antagonistic effect of citalopram and clomipramine against fenfluramine-induced hyperthermia might be connected with their effect on the uptake of 5-HT.

Topics: Adaptation, Physiological; Amitriptyline; Animals; Body Temperature; Citalopram; Clomipramine; Dose-Response Relationship, Drug; Hot Temperature; Male; Piperazines; Piperidines; Propylamines; Quipazine; Rats; Rats, Inbred Strains; Serotonin; Serotonin Antagonists

The mechanism of action of 5-hydroxytryptophan (5-HT, 10 mg/kg), quipazin (7 mg/kg), zimelidin (15 mg/kg) and m-chlorophenylpiperazine (5 mg/kg) was examined with the aid of some analyzer substances. The avoidance behavior under stress was used as criterion of estimation. The optimizing effect of 5-HT on the avoidance behavior was demonstrated to be a consequence of serotonin synthesis activation and its release with activation of postsynaptic 5-HT-1-receptors. An adverse effect of quipazin on the avoidance behavior was, to a greater degree, due to the activation of 5-HT-2-autoreceptors rather than of dopamine receptors. The inhibitory effect of m- chlorphenylpiperazine was reversed by administration of pyrenepyrone , a blocker of 5-HT-2-receptors. The inhibitory effect of zimelidine on the avoidance behavior was not removed by clonidin . The positive effect on the avoidance behavior under stress occurs as a result of exposures that activate the synthesis and release of 5-HT as well as of activation of postsynaptic 5-HT-1 receptors.

Topics: 5-Hydroxytryptophan; Acute Disease; Animals; Avoidance Learning; Cyproheptadine; Humans; Hydrazines; Male; Piperazines; Piperidines; Quinolines; Quipazine; Rats; Rats, Inbred Strains; Stress, Psychological; Tranquilizing Agents; Zimeldine

The pharmacological effects of two newly synthesized anorectic agents CM 57373 (4-amino-1-(6-bromopyrid-2-yl) piperidine hydrochloride) and CM 57493 (4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6 tetrahydrophyridine hydrochloride) have been studied. Both drugs decreased food intake dose dependently in rats deprived of food for 20 h/d. The doses that inhibited food intake by 50 percent (ID50) were 9.74 mg kg-1 p.o. for CM 57493 and 7.37 mg kg-1 p.o. for CM 57373. The general behaviour of the rats was not affected at anorectic doses and no amphetamine-like stimulation was observed. The anorectic effect of CM 57373 was selectively, but not completely, antagonized by metergoline and methysergide, two antagonists of serotoninergic receptors in the central nervous system. Neither noradrenaline antagonists (propranolol and phentolamine) nor a dopamine antagonist (penfluridol) affected the anorexia induced by CM 57373. These results indicate that the anorectic effect of CM 57373 is, at least, partially mediated by the serotoninergic system. The mechanism of action of CM 57493 is more complex, since several distinct neurotransmitter systems appear to be involved in its effect. In cross-tolerance experiments with fenfluramine, there was a reduction of the anorectic activity of CM 57493, suggesting similar mechanisms of action for these two drugs, even though pretreatment with metergoline or methysergide antagonized the anorectic effect of fenfluramine but not that of CM 57493. The anorectic effect of CM 57493 was antagonized by pretreatment with propranolol, a beta-noradrenergic antagonist, suggesting an involvement for the beta-noradrenergic system as well. Pretreatment with phentolamine or penfluridol did not modify the effect of CM 57493 on food intake. In-vitro and in-vivo biochemical studies showed that CM 57373 and CM 57493 act mainly on central serotoninergic mechanisms. CM 57373 is a serotonin releaser and a serotonin reuptake inhibitor. But, unlike fenfluramine which affects the storage pool for 5HT, it releases 5HT mainly from a functional pool. CM 57493 did not affect serotonin release and uptake but exhibited a high affinity to serotonin postsynaptic receptors.

Topics: Animals; Appetite Depressants; Dextroamphetamine; Drug Tolerance; Eating; Female; Fenfluramine; Lethal Dose 50; Metergoline; Methysergide; Penfluridol; Phentolamine; Piperazines; Piperidines; Propranolol; Pyridines; Rats; Rats, Inbred Strains; Serotonin

The data are provided on the effect of some serotoninergic substances on the avoidance behavior under acute stress. 5-Hydroxytryptophan, zimelidine (low doses), pyrenepyron, ciproheptadine, trazodon (high doses), produced a noticeable positive action on the behavior pattern under study. Quipazin and zimelidine (high doses) provoked an increase in the number of affective manifestations and a rise of the latent avoidance time. Regardless of an appreciable fall in the number of affective manifestations, the powerful sedative effect of m-chlorphenylpiperazine led to an increase in the latent response periods. It was shown that substances that produced a direct or mediated activation effect on the serotoninergic system had an appreciable favourable influence on the avoidance behavior, which was a consequence of a decrease in the animals' emotional excitement. Combination of serotonin-blocking properties (action on S2-autoreceptors) and dopaminergic properties brought about optimal results, provided that pyrenepyron was applied.

Topics: 5-Hydroxytryptophan; Animals; Antidepressive Agents; Brompheniramine; Cyproheptadine; Escape Reaction; Humans; Male; Piperazines; Piperidines; Quipazine; Rats; Rats, Inbred Strains; Serotonin; Stress, Psychological; Tranquilizing Agents; Trazodone; Zimeldine

4-(3-Indolyl-2-ethyl) piperidine (LM 5008), 2-(1-piperazinyl) quinoline (quipazine), and metachlorophenylpiperazine (mCPP) were studied for their ability to affect serotonergic mechanisms in vitro. Their relative potency in inhibiting serotonin (5-HT) uptake in vivo and reducing food intake in rats was also examined. mCPP was very potent in displacing 3H-5-HT bound to brain membranes (IC50, 6.2 X 10(-7) M), followed by quipazine, which showed an IC50 of 3.8 X 10(-6) M. LM 5008 was the least effective with an IC50 of 3.6 X 10(-5) M. mCPP and quipazine were less potent than d-fenfluramine in releasing 14C-5-HT from brain synaptosomes, while LM 5008 caused no significant effects at a concentration of 10(-5) M. Conversely, both in vitro and in vivo studies on 5-HT uptake showed that LM 5008 was the most potent compound in inhibiting 5-HT uptake and mCPP the least potent. Since a 50% reduction of food intake was not reached even with a dose of LM 5008 27-times higher than the ED50 for inhibiting 5-HT uptake in vivo, it is suggested that even marked inhibition of 5-HT uptake at central synapses is not sufficient per se to trigger serotonin-dependent anorexia in the rat. Increased release and/or direct stimulation of post-synaptic receptors may be necessary to obtain this effect. This could be of interest for developing new agents which can cause anorexia by interacting with brain serotonin.

Topics: Animals; Anorexia; Brain; Feeding and Eating Disorders; Feeding Behavior; Female; Fenfluramine; Humans; Piperazines; Piperidines; Quipazine; Rats; Serotonin; Serotonin Antagonists; Synaptosomes; Time Factors

Topics: Animals; Anorexia; Appetite Depressants; Brain; Feeding Behavior; Fenfluramine; Piperazines; Piperidines; Quipazine; Rats; Receptors, Serotonin; Serotonin; Synaptosomes