Effect of ritanserin and leuprolide alone and combined on marble-burying behavior of mice.

Obsessive-compulsive disorder (OCD) is characterized by absurd, recurrent thoughts (obsessions) followed by certain stereotyped actions (compulsions). OCD can impair all areas of brain functioning and produce devastating effects on patients and their families. Marble-burying behavior of mice is a well-accepted paradigm to screen anti-compulsive activity. The aim of present study was to evaluate the effect of ritanserin and leuprolide per se and in combination on marble-burying behavior of mice. The present study showed that ritanserin (l, 2 and 20 mg kg(-1) i.p.) per se did not show any anti-compulsive effect. Leuprolide (200 and 300 microg kg(-1) s.c.) per se showed anti-compulsive effect, causing statistically significant inhibition of marble-burying behavior of mice. The prior treatment with ritanserin, 5HT(2A/2C) antagonist (20 mg kg(-1) i.p.), has effectively blocked the inhibitory influence of leuprolide (300 microg kg(-1) s.c.) on marble burying behavior of mice, suggesting that leuprolide, a LHRH agonist, also requires serotonin to express its anti-compulsive effect. Further, it also suggested that the effect of leuprolide appears to be mediated through 5HT(2A/2C) receptors.

Hypersensitivity of 5-HT2 receptors in OCD patients. An increased prolactin response after a challenge with meta-chlorophenylpiperazine and pre-treatment with ritanserin and placebo.

INTRODUCTION: Several studies in obsessive compulsive disorder (OCD) have provided circumstantial evidence that the 5-HT-system is involved in the pathophysiology of OCD. To further examine the role of 5-HT receptors we studied the behavioural and neuroendocrine effects of different doses of meta-chlorophenylpiperazine (mCPP) in OCD patients and healthy controls, after pre-treatment with ritanserin, a 5-HT2 receptor antagonist, and placebo. DESIGN: Twenty patients and 20 healthy controls received 0.1, 0.3 or 0.5 mg/kg mCPP or placebo orally. Each subject was tested two times, receiving both times the same dosage of mCPP or placebo with ritanserin or placebo pre-treatment. All was done under double-blind conditions. OC-symptoms and hormone levels were measured. RESULTS: The increase in prolactin level after mCPP administration was more robust in patients than in controls. The prolactin response following 0.5 mg/kg of mCPP was partially blocked by ritanserin in patients, but totally blocked in healthy controls. The cortisol responses in both groups did not differ statistically significant from each other and were entirely blocked by ritanserin. None of the subjects experienced an exacerbation of obsessive compulsive symptoms. CONCLUSION: The neuroendocrine results show an enhanced susceptibility of OCD patients for the mCPP-induced prolactin response, which effect seems to be due to an increased sensitivity of 5-HT2 receptors.

Anxiolytic-like effect of group III mGlu receptor antagonist is serotonin-dependent.

Literature data have provided evidence that antagonists of group I metabotropic glutamate receptors (mGluRs) and agonists of group II/III mGluRs show anxiolytic-like properties in preclinical studies. However data reporting anxiolytic-like action of group III mGlu receptor antagonists were also published. In the present paper we investigated the anxiolytic-like activity of the group III mGlu receptor antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG). To examine its anxiolytic-like effects, the basolateral amygdala was chosen as an injection site, as this brain region is involved in the regulation of anxiety-related behavior. To detect anxiolytic-like activity, the Vogel conflict-drinking test in rats was used. Intra-amygdalar injections of CPPG exhibited dose-dependent, potent anxiolytic-like action at a dose of 75 nmol, which was blocked by a concomitant administration of the group III mGlu receptor agonist CI (S,3R,4S)-1-aminocyclo-pentane-1,3,4-tricarboxylic acid (ACPT-I) at a dose of 7.5 nmol. The benzodiazepine receptor antagonist flumazenil (given intraperitoneally, 10 mg/kg) did not change the anxiolytic-like effect of CPPG, but that effect was abolished by the non-selective antagonist of 5-HT receptors metergoline and the antagonist of 5-HT2A/C receptors ritanserin (both given intraperitoneally at doses of 2 and 0.5 mg/kg, respectively). These findings suggest that the blockade of group III mGlu receptors in the amygdala is responsible for anxiolysis and that serotonergic, but not the benzodiazepine recognition site of the GABA-ergic system are involved in the anxiolytic-like response induced by group III mGlu antagonist.

Ameliorating effect of emodin, a constitute of Polygonatum multiflorum, on cycloheximide-induced impairment of memory consolidation in rats.

The aim of the present study was intended to investigate the ameliorating effects of emodin on memory consolidation via cholinergic, serotonergic and GABAergic neuronal systems in rats. First, we evaluated the ameliorating effects of emodin on cycloheximide (CXM)-induced impairment of passive avoidance response in rats. Secondly, we clarified the role of cholinergic, serotonergic or GABAergic system on the ameliorating effect of emodin by using 5-HT1A receptor partial agonist, 5-HT2 receptor antagonist, GABAB agonist, GABAA antagonist and muscarinic receptor antagonist. Emodin protected the rat from CXM-induced memory consolidation impairment. The beneficial effect of emodin on CXM-induced memory consolidation impairment was amplified by 8-OH-DPAT (5-HT1A receptor partial agonist) and ritanserin (5-HT2 receptor antagonist), but reduced by scopolamine. These results suggested that the beneficial effect of emodin on CXM-induced memory consolidation impairment was amplified by serotonergic 5-HT1A-receptor partial agonist and 5-HT2 receptor antagonist but reduced by muscarinic receptor antagonist.

Atypical antipsychotic clozapine reversed deficit on prepulse inhibition of the acoustic startle reflex produced by microinjection of DOI into the inferior colliculus in rats.

Dysfunctions of the serotonergic system have been suggested to be important in the neurobiology of schizophrenia. Patients with schizophrenia exhibit deficits in an operational measure of sensorimotor gating: prepulse inhibition (PPI) of startle. PPI is the normal reduction in the startle response caused by a low intensity non-startling stimulus (prepulse) which is presented shortly before the startle stimulus (pulse). The hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI), a 5-hydroxytryptamine(HT)2 receptor agonist disrupted PPI in rats. The inferior colliculus (IC) is a critical nucleus of the auditory pathway mediating acoustic PPI. The activation of the IC by the acoustic prepulse reduces startle magnitude. The present study investigated the role of serotonergic transmission in the IC on the expression of acoustic PPI. For that we investigated whether 5-HT2A receptor activation or blockade would affect this response. Unilateral microinjection of DOI (10µg/0.3µl) into the IC disrupted PPI, while microinjection of the 5-HT2A receptor antagonist ritanserin (4µg/0.3µl), into this structure did not alter PPI. We also examined the ability of the atypical antipsychotic clozapine (5.0mg/kg; I.P.) to reverse the disruption of PPI produced by unilateral microinjections of DOI into the IC of rats. Pretreatment with clozapine blocked DOI-induced disruption of PPI. Altogether, these results suggest that serotonin-mediated mechanisms of the IC are involved in the expression of PPI in rodents and that this response is sensitive to atypical antipsychotic clozapine.

Microinjection of ritanserin into the dorsal hippocampal CA1 and dentate gyrus decrease nociceptive behavior in adult male rat.

Prenatal 5HT depletion causes a significant decrease in the level of nociceptive sensitivity during the second phase of the formalin test behavioral response. These experiments were designed to test whether blocking 5HT2A/2c receptors in the CA1 region of the hippocampus and dentate gyrus would decrease nociceptive behaviors induced by a peripheral noxious stimulus formalin as an animal model of unremitting human being. The 5HT2A/2c receptor antagonist ritanserin (2, 4 and 8 microg/0.5 microl) was injected into the CA1 area and dentate gyrus of behaving rats 5 min before subcutaneous injection of formalin irritant. Nociceptive behaviors in both phases of the formalin test were significantly decreased by ritanserin (4 and 8 microg/0.5 microl) and ritanserin had no effect at 2 microg/0.5 microl. These results support the hypothesis that the hippocampal formation may modify the processing of incoming nociceptive information and that 5HT2A/2c receptor-sensitive mechanisms in the hippocampus may play a role in nociception and/or the expression of related behaviors.

Microinjection of ritanserin into the CA1 region of hippocampus improves scopolamine-induced amnesia in adult male rats.

The effect of ritanserin (5-HT2 antagonist) on scopolamine (muscarinic cholinergic antagonist)-induced amnesia in Morris water maze (MWM) was investigated. Rats were divided into eight groups and bilaterally cannulated into CA1 region of the hippocampus. One week later, they received repeatedly vehicles (saline, DMSO, saline+DMSO), scopolamine (2 microg/0.5 microl saline/side; 30 min before training), ritanserin (2, 4 and 8 microg/0.5 microl DMSO/side; 20 min before training) and scopolamine (2 microg/0.5 microl; 30 min before ritanserin injection)+ritanserin (4 microg/0.5 microl DMSO) through cannulae each day. Animals were tested for four consecutive days (4 trial/day) in MWM during which the position of hidden platform was unchanged. In the fifth day, the platform was elevated above the water surface in another position to evaluate the function of motor, motivational and visual systems. The results showed a significant increase in escape latencies and traveled distances to find platform in scopolamine-treated group as compared to saline group. Ritanserin-treated rats (4 microg/0.5 microl/side) showed a significant decrease in the mentioned parameters as compared to DMSO-treated group. However, scopolamine and ritanserin co-administration resulted in a significant decrease in escape latencies and traveled distances as compared to the scopolamine-treated rats. Our findings show that microinjection of ritanserin into the CA1 region of the hippocampus improves the scopolamine-induced amnesia.

Behavioral effects of systemically administered MK-212 are prevented by ritanserin microinfusion into the basolateral amygdala of rats exposed to the elevated plus-maze.

RATIONALE: Although 5-HT2 receptors seem to play an important role in anxiety, results from numerous studies are still highly variable. Moreover, little is known about the behavioral effects of centrally administered 5-HT2 compounds in animal models of anxiety. OBJECTIVE: The current study was performed to: (1) further investigate the effects of 5-HT2 receptor activation in rats exposed to the elevated plus-maze (EPM) and the open-field arena, two widely used animal models for studying anxiety and locomotor activity; and (2) evaluate the involvement of the 5-HT2 receptors within the basolateral nucleus of the amygdala (BLA) in the modulation of such effects. METHODS: In the first experiment, male Wistar rats were exposed for 5 min to the EPM 27 min following intraperitoneal (i.p.) (1.0 ml/kg) injections of the preferential 5-HT2C receptor agonist 6-chloro-2[1-piperazinyl]pyrazine (MK-212) at doses of 1.0, 2.0, or 4.0 mg/kg. Control animals were injected with saline. The percentage of open-arm entries and the percentage of time spent in these arms were employed as anxiety indexes, whereas the number of closed-arm entries was calculated as indicative of locomotor activity. In the second experiment, rats were exposed for 10 min in an open-field arena to further assess the interference of the same MK-212 doses upon locomotor activity. In Experiment 3, rats were microinjected (0.2 microl) either with the mixed 5-HT 2A/2C receptor antagonist ritanserin (0.5, 1.25, 2.5, and 5.0 microg) or its vehicle into the BLA 12 min following i.p. injections of saline or the intermediate dose of MK-212 (2.0 mg/kg). Fifteen minutes later, each animal was exposed to the EPM as before. RESULTS: Whereas the highest dose of MK-212 (4.0 mg/kg) induced motor-suppressant effects in both EPM and open-field arena, the intermediate dose of the drug (2.0 mg/kg) reduced open-arm exploration without significantly affecting the number of closed-arm entries. This behavioral profile, consistent with selective anxiogenic effect in the EPM, was dose-dependently prevented by ritanserin microinfusion into the BLA. In saline-pretreated animals, however, ritanserin (all doses) was ineffective. CONCLUSIONS: MK-212 increases anxiety and decreases locomotor activity. The anxiogenic-like profile of 5-HT2 receptor activation is prevented by the blockade of 5-HT2 receptors within the BLA, which does not have an effect by itself upon basal anxiety levels triggered by the EPM.

The effect of intrahippocampal injections of ritanserin (5HT2A/2C antagonist) and granisetron (5HT3 antagonist) on learning as assessed in the spatial version of the water maze.

5HT(2A/2C) and 5HT(3) receptors have an important role in cognitive behavior specially in spatial learning and memory but the literature concerning the role of these receptors in hippocampus in cognition remains controversial. In the present study a 5HT(2A/2C) antagonist ritanserin (0, 2, 4, 8 microg/0.5 microl) and a 5HT(3) antagonist granisetron (0.0, 0.05, 0.25, 0.5 microg/0.5 microl) were injected bilaterally into the CA1 region of rat hippocampus, 20 min before each training session in Morris Water Maze (MWM) task. Compare with control group, ritanserin (4 microg/0.5 microl) significantly reduced the escape latency and traveled distance of swimming to platform, but granisetron (0.25 microg/0.5 microl) significantly increased those parameters. Both drugs had no effect on escape latency and traveled distance of a non-spatial visual discrimination task. These results suggest a differential role of 5HT(2A/2C) and 5HT(3) receptors during spatial learning that ritanserin improves rat performance in spatial discrimination task whereas granisetron impairs it.

The combination of agomelatine and ritanserin exerts a synergistic interaction in passive avoidance task.

Agomelatine is a potent agonist at melatonergic 1 and 2 (MT1 and MT2) receptors and an antagonist at serotonin-2C (5HT-2C) receptors. It was suggested that psychotropic effects of agomelatine is associated with its melatonergic and serotonergic effects. In this study, we aimed to evaluate the effects of agomelatine alone or in combination with ritanserin (5HT-2A/2C antagonist) on memory and learning. Male Balb-C mice (25-30 g) were used, and all drugs and saline were administrated by intraperitoneal (i.p.) route 30 min prior to evaluating retention time. Whilst agomelatine was administered at the doses of 1, 10 and 30 mg/kg, ritanserin was administered at the doses of 0.1, 1 and 10 mg/kg. To evaluate memory function, passive avoidance test was used. On the first day, acquisition time and on the second day (after 24h), retention time of mice were recorded. To evaluate the synergistic activity, only the least doses of agomelatine and ritanserine were used, that is, 1 and 0.1 mg/kg, respectively. Scopolamine (1 mg/kg) was used as a reference drug, so it was combined with drug groups. Our results show that 5HT-2A/2C receptor antagonist ritanserin (1 and 4 mg/kg, i.p.) and agomelatine (10 and 30 mg/kg, i.p.) improve memory deficit induced by scopolamine, whilst a synergistic interaction is observed between ritanserin and agomelatine (0.1 mg/kg and 1 mg/kg, i.p., respectively) when they were administered at their ineffective doses. According to our findings, we concluded that agomelatine improves memory deficit and thus improves the effect of agomelatine arises from its 5HT-2C receptor antagonist activity.

Antagonism of a PCP drug discrimination by hallucinogens and related drugs.

Drugs such as PCP and MK-801 can cause psychotic reactions in humans by antagonizing NMDA receptors. This action is ultimately toxic to certain cortical neurons and may be one mechanism underlying neurodegenerative diseases, including schizophrenia. It has been reported that hallucinogens such as LSD, DOM, and DOI can block the neurotoxic effects of NMDA antagonists, possibly by activating inhibitory 5-HT2A receptors on GABAergic interneurons that normally inhibit glutamatergic projections to the retrosplenial and cingulate cortexes. The purpose of this experiment was to determine the extent to which similar drugs might also alter the behavioral effects of one NMDA antagonist, PCP. Rats were trained to discriminate this compound (2.5 mg/kg) from saline and were then given a series of antagonist tests. It was found that LSD (0.32 mg/kg) and DOM (4.0 mg/kg) blocked the PCP cue completely; DMT (8.0 mg/kg) and a structural congener of LSD, lisuride (LHM; 0.4 mg/kg), blocked the effects of PCP partially. The 5-HT/DA antagonists spiperone and ritanserin had no effect on the PCP cue. These data suggest that LSD, DOM, and, less effectively, DMT and LHM can block the behavioral as well as the neurotoxic effects of NMDA antagonists most likely through agonist actions at 5-HT2 receptors.

Effects of acute and subchronic administration of ritanserin on the social behaviour of mice.

The effects of ritanserin on the behaviour of adult male CD1 mice were examined after acute intraperitoneal injection (0.1, 0.3 and 0.6 mg/kg) and after administration for 12-15 days in the drinking fluid at 1.6 mg/l (0.32 mg/kg daily) and 3.1 mg/l (0.7 mg/kg daily). The behaviour of each mouse was examined by ethological procedures during 5 min social encounters with an untreated partner in an aversive situation, an unfamiliar neutral cage, and in a familiar situation, the animal's home cage. Behaviour also was monitored for 5 min in the light-dark box. In the acute studies, behavioural observations commenced at 30 min after injection. In the home cage, ritanserin significantly increased social investigation during social encounters and reduced exploratory activity at all doses tested, after both acute and subchronic administration. In the neutral cage, acutely administered ritanserin increased social investigation and reduced non-social activity at all dose levels. Effects were maximal at 0.3 mg/kg, and at this dose it also increased aggression. In the neutral cage after subchronic administration, ritanserin at both dose levels increased aggression, digging and investigation of the substrate and occurrence of the social act, "attend", while reducing the time spent in non-social exploration. Ritanserin did not affect behaviour in the light-dark box. The significance of these findings relative to the anxiolytic and antidepressant effects of ritanserin is discussed.

Respiratory and cardiovascular effects of the mu-opioid receptor agonist [Lys7]dermorphin in awake rats.

1. Changes in respiratory variables, arterial blood pressure and heart rate were studied in awake rats after injection of the opioid peptide [Lys7]dermorphin and its main metabolites, [1-5]dermorphin and [1-4]dermorphin. 2. Fifteen minutes after injection, doses of [Lys7]dermorphin producing antinociception (i.c.v., 36-120 nmol; s.c., 0.12-4.7 micromol kg(-1)) significantly increased respiratory frequency and minute volume of rats breathing air or hypoxic inspirates. This respiratory stimulation was reversed to depression by the 5-HT receptor antagonist ritanserin (2 mg kg(-1), s.c.), was blocked by naloxone (0.1 mg kg(-1), s.c.), significantly reduced by the mu1 opioid receptor antagonist naloxonazine (10 mg kg(-1), s.c., 24 h before) but unaffected by peripherally acting opioid antagonist naloxone methyl bromide (3 mg kg(-1), s.c.). Forty five minutes after injection, doses of the peptide producing catalepsy (s.c., 8.3-14.2 micromol kg(-1), i.c.v., 360 nmol) significantly reduced respiratory frequency and volume of rats breathing air and blocked the hypercapnic ventilator response of rats breathing from 4% to 10% CO2. I.c.v. administration of [1-5]dermorphin and [1-4]dermorphin (from 36 to 360 nmol) never stimulated respiration but significantly reduced basal and CO2-stimulated ventilation. Opioid respiratory depression was only antagonized by naloxone. 3. In awake rats, [Lys7]dermorphin (0.1-1 mg kg(-1), s.c.) decreased blood pressure. This hypotensive response was abolished by naloxone, reduced by naloxone methyl bromide and unaffected by naloxonazine. 4. In conclusion, the present study indicates that analgesic doses of [Lys7]dermorphin stimulate respiration by activating central mu1 opioid receptors and this respiratory stimulation involves a forebrain 5-hydroxytryptaminergic excitatory pathway.

A quantitative evaluation of the relationships between growth hormone secretion and delta wave electroencephalographic activity during normal sleep and after enrichment in delta waves.

The existence of a relationship between growth hormone (GH) release and slow-wave sleep (SWS), often studied in the past using conventional scoring of sleep stages, remains controversial. In the present study, this relationship was reevaluated by spectral analysis of the sleep electroencephalogram (EEG) and deconvolution analysis of the plasma GH concentrations during normal nocturnal sleep and after enrichment in SWS by means of ritanserin, a selective 5-HT2 receptor antagonist. Eight healthy male subjects each participated in two randomized night studies after having received either a placebo or a 5-mg dose of ritanserin. They were subjected to 8 hours of polysomnography, including spectral analysis of the sleep EEG. Plasma GH levels were measured at 10-minute intervals. The mean delta absolute power and the mean GH secretory rates were significantly higher under ritanserin than under placebo for the first 3 hours after sleep onset (+24% and +29%, respectively). Their nocturnal profiles were significantly and positively correlated in all subjects (average r = 0.710 under placebo, 0.567 under ritanserin; p < 0.0001 in both cases). GH secretory pulses were found to be coincident with delta activity peaks in both directions. The amount of GH secreted during significant GH pulses was correlated with the amount of concomitant delta wave activity (r = 0.803 under placebo, r = 0.764 under ritanserin, p < 0.0001). Similarly, the amount of delta wave activity found during delta wave peaks was correlated with the amount of GH secreted concomitantly (r = 0.715 under placebo, r = 0.723 under ritanserin: p < 0.0001). These results demonstrate a close temporal and quantitative relationship between GH secretion and delta wave activity, which may be evidence of common stimulatory mechanisms.

Involvement of the serotonergic neuronal system in phencyclidine-induced place aversion in rats.

The possible involvement of the serotonergic neuronal system in aversive motivation produced by phencyclidine [1-(1-phenylcyclohexyl)piperidine; PCP] was investigated using a place-conditioning paradigm in rats. PCP (4 mg/kg, i.p.) produced place aversion in this task as reported previously (Kitaichi K, Noda Y, Hasegawa T, Furukawa H, Nabeshima T. Acute phencyclidine induces aversion, but repeated phencyclidine induces preference in the place conditioning test in rats. Eur J Pharmacol 1996;318:7-9). The blockade of serotonin2A (5-HT2A) receptors using the antagonist ritanserin (3 and 10 mg/kg, p.o.) significantly attenuated this aversive property of PCP whereas lesions of serotonergic neurons using 5,7-dihydroxytryptamine (5,7-DHT, 100 microg/animal, i.c.v.) failed to affect it. Repeated PCP treatment (10 mg/kg, i.p. for 14 days), which is enough to diminish the stereotyped 5-HT2A receptor-mediated head-twitch behavior, also decreased the place aversion. These results suggest that the serotonergic neuronal system, specifically the 5-HT2A receptor, may play a critical role in producing PCP-induced place aversion.

Neuronal mechanism of the inhibitory effect of calcitonin on N-methyl-D-aspartate-induced aversive behavior.

To elucidate the mechanism of antinociceptive effects of calcitonin, we investigated whether receptor antagonists for various neurotransmitter receptors alter the inhibitory effect of calcitonin on intrathecally injected N-methyl-D-aspartate-induced aversive behavior in mice. Neither naloxone, an opioid receptor antagonist, phentolamine and benextramine, alpha-adrenoceptor antagonists, nor ritanserin, a 5-HT2A receptor antagonist, inhibited the calcitonin-induced anti-aversive effects. Pindolol and (--)-propranolol, non-selective antagonists of beta-adrenoceptors and 5-HT1 receptors, 1-(2-methoxyphenyl)-4-[4-(2-phethalimido) butyl]-piperazine hydrobromide (NAN-190), a 5-HT1A receptor antagonist, 3-tropanyl-3,5-dichlorobenzoate (MDL72222) and metoclopramide, 5-HT3 receptor antagonists, significantly inhibited the calcitonin-induced anti-aversive effects. (--)-Bicuculline, a GABAA receptor antagonist, phaclofen and 5-aminovaleric acid, GABAB receptor antagonists, also attenuated the calcitonin-induced anti-aversive effects. These results suggest that beta-adrenoceptor, 5-HT1A, 5-HT3, GABAA and GABAB receptors, but not alpha-adrenoceptor, opioid nor 5-HT2A receptors, are involved in the inhibitory effect of calcitonin on intrathecally injected N-methyl-D-aspartate-induced aversive behavior in mice.

Temporal link between plasma thyrotropin levels and electroencephalographic activity in man.

Plasma thyrotropin (TSH) levels have been previously shown to be associated with the internal sleep structure determined by conventional scoring of sleep stages. This temporal relationship was re-evaluated using spectral analysis of the sleep electroencephalogram (EEG). Eight healthy male subjects underwent two randomized night studies after having received either placebo or 5 mg ritanserin, a selective 5-HT2 receptor antagonist known to increase slow-wave sleep. Delta relative power and TSH levels, determined at 10 min intervals, were found to be inversely related with an average cross-correlation coefficient highly significant (P < 0.0001) in both experimental conditions. Alpha slow-wave index, an estimator of awakenings, and TSH pulses exhibited a significant temporal association in both conditions. These results demonstrate that TSH fluctuations are linked to the sleep EEG activity in man.

Ritanserin administration potentiates amphetamine-stimulated dopamine release in the rat prefrontal cortex.

1. Administration of serotonin 5-HT2 receptor antagonists increases the basal release of dopamine in the mesocorticolimbic pathway. 2. Treatment with dopamine D2 receptor antagonists increases impulse-dependent basal dopamine release in the nigrostriatal pathway. D2 antagonists also potentiate carrier-mediated increases in DA efflux from this pathway. 3. The present study compared the effects of a 5-HT2A/C antagonist (ritanserin) and a D2 antagonist (haloperidol) on carrier-mediated (amphetamine-induced) DA release in the mesocortical system. 4. In vivo microdialysis was used to recover extracellular fluid from the medial prefrontal cortex of conscious rats. Samples were then assayed for dopamine content by HPLC with electrochemical detection. Haloperidol or ritanserin were administered systemically (i.p.) 30 min before d-amphetamine (5.0 mg/kg i.p.). 5. Results demonstrated that 5.0 mg/kg ritanserin, but not 1.0 mg/kg, potentiated amphetamine-induced DA release in the prefrontal cortex. Similar to previous findings in the striatum, haloperidol (1.0 mg/kg) also augmented amphetamine-stimulated DA efflux in the cortex. 6. These results suggest that 5-HT2 and D2 receptor antagonists increase impulse-mediated dopamine release in the rat prefrontal cortex which in turn potentiates carrier-mediated release.

Ritanserin, a central 5-HT2 antagonist, in heavy social drinkers: desire to drink, alcohol intake and related effects.

Ritanserin, a 5-HT2 receptor antagonist, decreased alcohol intake in some, but not all, animal studies and in an open clinical study. We tested the short-term effects of ritanserin in 39 (35 male, four female) heavy social drinkers (consuming at least 28 drinks/week), aged 19-63 years, who were not seeking treatment. After an intake assessment, they received placebo for 7 days in a single-blind baseline. They were then randomly assigned to one of three double-blind treatments for 14 days: ritanserin 5 mg/day (n = 12), ritanserin 10 mg/day (n = 13) or placebo (n = 14). Subjects recorded daily outpatient alcohol intake. Feelings of intoxication and interest, desire, craving and liking for alcohol were rated retrospectively at each weekly study visit. Experimental drinking sessions were conducted after baseline (EDS1) and treatment (EDS2); in each session subjects were offered 18 mini-drinks (total = six standard) and rated their desire to drink, intoxication and mood (POMS). Outpatient results: ritanserin 5 mg/day decreased desire and craving for alcohol (vs. baseline, p < 0.05) but not alcohol intake. Liking of alcohol decreased from baseline with ritanserin 10 mg/day (p = 0.01) and placebo (p = 0.05). Changes in alcohol intake from baseline with ritanserin 10 mg/day (increase, p > 0.05) and placebo (decrease, p > 0.05) were different (p < 0.05). EDS results: in EDS2, desire ratings for the first three mini-drinks were lower after ritanserin 5 mg/day than after ritanserin 10 mg/day (p < 0.05), but the decreases were not statistically significant when EDS1 desire ratings were controlled for. Ritanserin 10 mg/day increased alcohol-induced feelings of intoxication and friendliness, compared with placebo (p < 0.05). Both ritanserin 5 mg/day and 10 mg/day enhanced alcohol-induced decreases in fatigue, compared with placebo (p < 0.05). These results indicate that ritanserin may have differential effects on alcohol intake, desire, craving and liking, intoxication and some of alcohol's effects on mood. However, they suggest that ritanserin has limited efficacy in reducing alcohol intake in heavy drinkers.

Effects of ritanserin on the behavioral, neuroendocrine, and cardiovascular responses to meta-chlorophenylpiperazine in healthy human subjects.

Ten healthy male subjects were administered i.v. meta-chlorophenylpiperazine (MCPP) (0.1 mg/kg) after oral ritanserin (5-10 mg), a putative 5HT1c/5HT2 (serotonin) antagonist, or placebo. Behavioral responses, cardiovascular effects, and neuroendocrine responses (cortisol, growth hormone, and prolactin) were measured serially for 4 hours after MCPP infusion. Premedication with ritanserin attenuated the MCPP-induced increases in self-rated anxiety and prolactin, and completely antagonized MCPP cortisol elevations. In contrast, ritanserin did not significantly alter growth hormone response to MCPP. These findings suggest a role for 5-HT1c/5-HT2 receptors in the endocrine and behavioral responses to the mixed serotonin agonist MCPP in humans.