fluvoxamine and 1-(3-chlorophenyl)piperazine

Some selective serotonin reuptake inhibitors (SSRIs) have recently been approved for the treatment of anxiety disorders such as obsessive-compulsive disorder, panic disorder and social anxiety disorder, and they are considered first-line treatment for anxiety disorders in Japan as well as in other countries. Previous clinical studies have suggested that the 5-HT2C receptors in subjects with anxiety disorders are hypersensitive. We recently reported that chronic treatment with fluvoxamine or paroxetine desensitized 5-HT2C receptor function. The desensitization of 5-H T2C receptor function has also been reported with other SSRIs and is considered to be a common mechanism of action of SSRIs in the treatment of anxiety disorders. In addition, some studies have suggested that 5-HT2A receptors and 5-HTIA receptors participate in anxiety disorders and the therapeutic mechanism. Both clinical studies and animal studies have indicated that the amygdala plays an essential role in anxiety and fear response. Thus, it may be important to elucidate functional changes in these 5-HT receptor subtypes in brain regions including the amygdala under the chronic administration of SSRIs to understand the anxiolytic mechanism of SSRIs.

Topics: Animals; Anxiety Disorders; Fluvoxamine; Humans; Piperazines; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Receptor, Serotonin, 5-HT2C; Selective Serotonin Reuptake Inhibitors; Serotonin Receptor Agonists

Obsessive Compulsive Disorder (OCD) is characterized by recurrent, anxiety-producing thoughts accompanied by unwanted, overwhelming urges to perform ritualistic behaviors. Pharmacological treatments for this disorder (serotonin uptake inhibitors) are problematic because there is a 6-8 week delayed onset and half of the patients do not adequately respond. The present study evaluated whether Ritualistic Chewing Behaviors (RCBs) induced by the serotonin agonist mCPP in the rat is a behavioral model for OCD. The effects upon the RCBs induced by mCPP (1 mg/kg) were evaluated following treatments with either the serotonin antagonist mianserin (3 mg/kg), the dopamine antagonist haloperidol (1 mg/kg), the GABA modulator diazepam (10 mg/kg), or the serotonin uptake inhibitors clomipramine and fluvoxamine (15 mg/kg). The response to mCPP was blocked by acute treatment with mianserin, but not with acute haloperidol or diazepam. Further experiments revealed that the effects of mCPP were blocked by chronic, but not acute, treatment with clomipramine and fluvoxamine. A time-course demonstrated that 14 days of chronic treatment were required for blockade of the mCPP-evoked response. The current study demonstrates that mCPP-evoked RCBs may be a rodent model for OCD that can be used to predict the clinical efficacy and time course of novel OCD treatment. Future investigations may be able to use the current model as a tool for bench-marking corresponding changes in other measures of neurological activity that may provide insight into the mechanisms underlying OCD.

Topics: Animals; Behavior, Animal; Clomipramine; Diazepam; Disease Models, Animal; Dopamine Antagonists; Fluvoxamine; GABA Modulators; Haloperidol; Male; Mastication; Mianserin; Obsessive-Compulsive Disorder; Piperazines; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists; Serotonin Receptor Agonists

Serotonin (5-hydroxytryptamine; 5-HT) 2C receptors and the downstream melanocortin pathway are suggested to mediate the anorexic effects of m-chlorophenylpiperazine (mCPP) and fenfluramine. We previously reported that fluvoxamine, a selective serotonin reuptake inhibitor, together with pharmacological inactivation of 5-HT2C receptors exert feeding suppression through activation of 5-HT1B receptors in mice. Here, we report that fluvoxamine exerted anorexic effects in 5-HT2C receptor mutant mice with heterozygous mutation of beta-endorphin gene (2CREnd mice), whereas fluvoxamine had no effect on food intake in age-matched wild-type mice and 5-HT2C receptor mutant mice, which are associated with decreases in hypothalamic proopiomelanocortin (POMC) expression. mCPP suppressed food intake in 5-HT2C receptor mutant mice, 2CREnd mice and age-matched wild-type mice. These results suggest that fluvoxamine-induced feeding suppression requires a perturbation of 5-HT2C receptor and beta-endorphin signalling plus functional hypothalamic POMC activity, whereas mCPP-induced feeding suppression does not always require functional 5-HT2C receptor, beta-endorphin, and POMC activity in mice.

Topics: Animals; Antidepressive Agents, Second-Generation; Appetite Depressants; beta-Endorphin; Eating; Fluvoxamine; Hypothalamus; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Piperazines; Pro-Opiomelanocortin; Receptor, Serotonin, 5-HT2C; Serotonin Receptor Agonists

Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat anxiety and depressive disorders. These agents may cause upper gastrointestinal (GI) symptoms that lead to their discontinuation. We examined whether SSRIs modify physiologic GI motor activities in freely moving rats.. The SSRIs fenfluramine, fluvoxamine, paroxetine, and fluoxetine were administered to 24-hour food-deprived rats, and then GI motility was measured in conscious, freely moving rats using a strain gauge force transducer method. Plasma acyl ghrelin levels were determined by enzyme immunoassay.. Plasma acyl ghrelin levels were analyzed in conjunction with fasted motor activities. Acyl ghrelin was increased in association with the occurrence of Phase III-like contractions of the migrating motor complex in the antrum and duodenum. SSRIs decreased acyl ghrelin and changed Phase III-like contractions to fed-like motor activities. Both effects were blocked by 5-HT2c, but not 5-HT1b, receptor antagonist. Neither melanocortin 4 nor the 3/4 receptor antagonists blocked this motor effect, although they restored the anorexia induced by SSRIs. The improving effect on GI motility by 5-HT2c receptor (5-HT2cR) antagonist disappeared after treatment with a growth-hormone secretagogue receptor antagonist, whereas ghrelin or ghrelin-releasing drug such as TJ-43 changed SSRI-induced fed-like motor activities to fasted activities.. SSRIs have inhibitory effects on acyl ghrelin and GI motor activities through 5-HT2cR. Our study identifies the importance and divergence of central 5-HT2cR pathways that regulate GI motor activities through ghrelin and feeding/energy metabolism via melanocortin 4 receptor signaling.

Topics: Animals; Drugs, Chinese Herbal; Eating; Fenfluramine; Fluoxetine; Fluvoxamine; Gastrointestinal Motility; Ghrelin; Growth Hormone; Injections, Intraventricular; Male; Oligopeptides; Paroxetine; Piperazines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2C; Receptors, Ghrelin; Selective Serotonin Reuptake Inhibitors; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists

Serotonin (5-hydroxytryptamine; 5-HT) 2C receptors and the downstream melanocortin pathway are suggested to mediate the appetite-suppressing effects of 5-HT drugs such as m-chlorophenylpiperazine (mCPP) and fenfluramine. Here, we report that fluvoxamine (3-30 mg/kg), a selective serotonin reuptake inhibitor (SSRI), in the presence of SB 242084 (1-2 mg/kg), a selective 5-HT2C receptor antagonist, exerts appetite-suppressing effects while fluvoxamine or SB 242084 alone has no effect. The appetite-suppressing effects were attenuated in the presence of SB 224289 (5 mg/kg), a selective 5-HT1B receptor antagonist. Moreover, CP 94253 (5-10 mg/kg), a selective 5-HT1B receptor agonist, exerted appetite-suppressing effects and significantly increased hypothalamic pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) gene expression and decreased hypothalamic orexin gene expression. These results suggest that fluvoxamine and inactivation of 5-HT2C receptors exert feeding suppression through activation of 5-HT1B receptors, and that 5-HT1B receptors up-regulate hypothalamic POMC and CART gene expression and down-regulate hypothalamic orexin gene expression in mice.

Topics: Analysis of Variance; Animals; Appetite Depressants; Behavior, Animal; Dose-Response Relationship, Drug; Drug Interactions; Eating; Fluvoxamine; Gene Expression Regulation; Intracellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Neuropeptides; Orexins; Piperazines; Piperidones; Pro-Opiomelanocortin; Receptor, Serotonin, 5-HT1B; Selective Serotonin Reuptake Inhibitors; Serotonin Receptor Agonists; Spiro Compounds; Time Factors

The effectiveness of fluvoxamine, a selective serotonin re-uptake inhibitor (SSRI), in the treatment of anxiety disorders, such as obsessive-compulsive, panic and social anxiety disorders, has been confirmed in clinical studies. The hypersensitivity of 5-HT2C receptors has been reported in subjects with these disorders, and SSRIs have been suggested to have therapeutic effects in such cases through the desensitization of the 5-HT2C receptor function. In the present study, we investigated whether chronic administration of fluvoxamine desensitizes 5-HT2C receptors using a putative in vivo rat model of 5-HT2C receptor function. Acute treatment with fluvoxamine or another SSRI, paroxetine, reduced spontaneous locomotion, as observed with the administration of m-chlorophenylpiperazine (mCPP). This effect of fluvoxamine was reversed by treatment with a selective 5-HT2C receptor antagonist, SB 242084. On the other hand, chronic treatment with fluvoxamine or paroxetine inhibited mCPP-induced hypolocomotion, while they had no effects in control rats. In addition, chronic treatment with these drugs had no effects on the mCPP concentration in the rat brain. These results suggest that 5-HT2C receptors are desensitized by chronic treatment with fluvoxamine, as well as paroxetine. Thus, the clinical efficacy of fluvoxamine on anxiety disorders might involve the normalization of the 5-HT2C receptor function.

Topics: Animals; Brain; Dose-Response Relationship, Drug; Fluvoxamine; Hypokinesia; Male; Motor Activity; Paroxetine; Piperazines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C; Selective Serotonin Reuptake Inhibitors; Serotonin Receptor Agonists

Twelve homing pigeons were trained to discriminate the 5-HT1A receptor agonist flesinoxan (0.25 mg/kg p.o.) from its vehicle in a fixed ratio (FR) 30 two-key operant drug discrimination procedure. Tests for generalization and antagonism showed that compounds with agonistic action at the 5-HT1A receptor, such as 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), buspirone and ipsapirone all substituted for the flesinoxan cue. Compounds with mixed agonistic action at the 5-HT(1A/1B) receptor fully (eltoprazine) or partially (RU24969 (5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl-1H-indole)) substituted for flesinoxan. TFMPP (1-(3-trifluoromethylphenyl)piperazine) and mCPP (1-(3-chlorophenyl)piperazine), both acting at the 5-HT(1B/2C) receptor, did not substitute for flesinoxan, neither did the selective 5-HT re-uptake inhibitor fluvoxamine. The results of the antagonism tests showed that the 5-HT1A receptor antagonists NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine), WAY 100635 ((N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo-he xane-carboxamide) and the newly developed DU125530 (2-[4-[4-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl ]butyl]-1,2-benzisothiazol-3(2H)-one-1,1-dioxide) fully (more than 80%) blocked the flesinoxan cue without having substantial effects when given alone. WAY100135 (N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide ), (+/-)-pindolol and (S)-UH-301 ((S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin) all partially antagonized the flesinoxan cue. However, both WAY100135 as well as (+/-)-pindolol also partially substituted for flesinoxan in generalization tests. NAN190, (S)-UH-301, WAY100635 and DU125530 were without any activity in the generalization test at the doses tested. The putative 5-HT1A receptor antagonist S15535 (4-benzodioxan-5-yl) 1-(indan-2-yl)piperazine) was identified as a full agonist in the present procedure. Taken together these results suggest that the flesinoxan cue in pigeons is mediated by the 5-HT1A receptor and that DU125530 acts as a full antagonist on the 5-HT1A receptor.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Buspirone; Columbidae; Discrimination Learning; Fluvoxamine; Indoles; Pindolol; Piperazines; Pyridines; Pyrimidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin Antagonists; Serotonin Receptor Agonists; Thiazoles

1. The effects of 5-hydroxytryptamine (5-HT) uptake inhibitors, agonists and antagonists have been evaluated on mouse marble-burying behaviour, a putative test for anxiolytic agents. The high levels of locomotor activity occurring on first exposure to a circular runway (runway were used as a separate test of non-specific drug effects. 2. Fluvoxamine, zimeldine, indalpine and citalopram dose-dependently inhibited burying without affecting runway activity. 5-Hydroxytryptophan (5-HTP, with carbidopa), 5-methoxy-N,N-dimethyltryptamine, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT), buspirione, gepirone and ipsapirone reduced burying only at doses reducing runway activity. RU 24969 increased runway activity at all effective doses. 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI), 1,-(3-trifluoromethylphenyl) piperazine (TFMPP) and 1-(3-chlorophenyl)-piperazine (mCPP) potently and differentially reduced burying at doses below those affecting runway activity. 3. 5-HT antagonists only reduced burying at high doses which also reduced runway activity. Burying inhibition by DOI was antagonized by ritanserin, ICI 169,369 and cyproheptadine but not by pindolol or a low (0.25 mg kg-1) dose of metergoline. Burying inhibition by mCPP was not altered by any of these agents except that it was potentiated by pindolol 5 mg kg-1. 4. Zimeldine burying inhibition was potentiated by ritanserine, ICI 169,369, ICS 205-930, cyproheptadine and pindolol. Runway activity was not affected by these drug combinations. 5. Zimeldine was administered in drinking water at a dose of 10 mg kg-1 daily for 21 days. Burying inhibition had disappeared by day 14 and did not recur 24 or 48h after withdrawal at which times responses to DOI were at control levels.6. Selective inhibition of marble burying was not found to be a property of 5-HT-related putative and actual anxiolytics such as buspirone, gepirone, ipsapirone, ritanserin and ondansetron. Nevertheless it was a general property of both 5-HT uptake inhibitors and 5-HT releasing agents; this generality suggests that elevated synaptic 5-HT could be responsible for the effects of these latter agents. The action of DOI may be attributable to effects at the 5-HT2 receptor but those of the 5-HT agonist and releasing agent mCPP, and the uptake inhibitor zimeldine, could not be attributed to effects at any one 5-HT receptor subtype. This, together with the potentiating effect of several 5-HT antagonists on the response to zimeldine, raises th

Topics: 5-Hydroxytryptophan; Amphetamines; Animals; Anti-Anxiety Agents; Behavior, Animal; Dose-Response Relationship, Drug; Drug Interactions; Female; Fenfluramine; Fluvoxamine; Mice; Motor Activity; Piperazines; Serotonin; Serotonin Antagonists; Zimeldine