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.

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.

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.

5-HT2A receptor antagonists improve motor impairments in the MPTP mouse model of Parkinson's disease.

Clinical observations have suggested that ritanserin, a 5-HT(2A/C) receptor antagonist may reduce motor deficits in persons with Parkinson's Disease (PD). To better understand the potential antiparkinsonian actions of ritanserin, we compared the effects of ritanserin with the selective 5-HT(2A) receptor antagonist M100907 and the selective 5-HT(2C) receptor antagonist SB 206553 on motor impairments in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP-treated mice exhibited decreased performance on the beam-walking apparatus. These motor deficits were reversed by acute treatment with L-3,4-dihydroxyphenylalanine (levodopa). Both the mixed 5-HT(2A/C) antagonist ritanserin and the selective 5-HT(2A) antagonist M100907 improved motor performance on the beam-walking apparatus. In contrast, SB 206553 was ineffective in improving the motor deficits in MPTP-treated mice. These data suggest that 5-HT(2A) receptor antagonists may represent a novel approach to ameliorate motor symptoms of Parkinson's disease.

Sedative and hypothermic effects of gamma-hydroxybutyrate (GHB) in rats alone and in combination with other drugs: assessment using biotelemetry.

The recreational drug gamma-hydroxybutyrate (GHB) has euphoric effects and can induce sedation and body temperature changes. GHB is frequently combined with other recreational drugs although these interactions are not well characterised. The present study used biotelemetry to provide a fine-grained analysis of the effects of GHB on body temperature and locomotor activity in freely moving rats, and investigated interactions between GHB and 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine (METH) and various antagonist drugs. GHB (1000mg/kg) caused profound sedation for more than 2h and a complex triphasic effect on body temperature: an initial hypothermia (5-40min), followed by hyperthermia (40-140min), followed again by hypothermia (140-360min). A lower GHB dose (500mg/kg) also caused sedation but only a hypothermic effect that lasted up to 6h. The dopamine D(1) receptor antagonist SCH 23390 (1mg/kg), the opioid antagonist naltrexone (1mg/kg), the benzodiazepine antagonist flumazenil (10mg/kg), and the 5-HT(2A/2C) receptor antagonist ritanserin (1mg/kg) did not prevent the overall sedative or body temperature effects of GHB (1000mg/kg). However the GABA(B) antagonist SCH 50911 (50mg/kg) prevented the hyperthermia induced by GHB (1000mg/kg). Repeated daily administration of GHB (1000mg/kg) produced tolerance to the sedative and hyperthermic effects of the drug and cross-tolerance to the sedative effects of the GABA(B) receptor agonist baclofen (10mg/kg). A high ambient temperature of 28 degrees C prevented the hypothermia obtained with GHB (500mg/kg) at 20 degrees C, while GHB (500mg/kg) reduced the hyperthermia and hyperactivity produced by co-administered doses of MDMA (5mg/kg) or METH (1mg/kg) at 28 degrees C. These results further confirm a role for GABA(B) receptors in the hypothermic and sedative effects of GHB and show an interaction between GHB and MDMA, and GHB and METH, that may be relevant to the experience of recreational users who mix these drugs.

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.

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.

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.

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.

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.

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.

Ritanserin improves sleep quality in narcolepsy.

A recent study in narcolepsy patients has shown that ritanserin, a 5HT2-antagonist, reduced wake after sleep onset times and subjective sleepiness during daytime. To assess the efficacy of this compound in a statistically sufficient number of narcoleptic patients a double-blind, placebo-controlled, European multi-center study on the effects of ritanserin on daytime sleepiness, the feeling of being refreshed in the morning, number of unwanted sleep periods and slow-wave sleep was performed. All 134 narcolepsy patients were allowed to remain on stable concomitant antidepressant, stimulant and gammahydroxybutyrate medication during the trial. Patients were randomly assigned to treatment with 5 mg or 10 mg ritanserin or placebo given once daily for 28 days. Efficacy was measured by two 40-hour polysomnographic recordings, visual analogue scales and physician, partner, parents and patient-rated sleep-wake behavior tests prior to and after the trial. Patients kept diaries on sleepiness, numbers of wanted and unwanted sleep periods, feeling of being refreshed and frequency of narcoleptic symptoms during the entire treatment period. Treatment with 5 and 10 mg ritanserin significantly improved the 'feeling of being refreshed in the morning,' but no other narcoleptic symptoms as assessed in the diary. Whereas investigators had the impression that the primary efficacy parameters were not improved by ritanserin, patients reported significant improvements in four out of six parameters, and patients partners in two out of six parameters with 5 mg ritanserin compared to placebo. Both ritanserin doses resulted in a significant increase of nocturnal slow-wave sleep (percentage of total sleep time) and a significant, dose-dependent reduction in NREM stage 1 percentage during daytime sleep. The significant polysomnographic findings were not paralleled by changes in the subjective parameters daytime sleepiness or number of unplanned sleep periods. In contrast to the first study on narcoleptic patients, ritanserin only improved one subjective parameter, but did not improve objective sleep quality or number of "sleep attacks" or reduce "wake after sleep onset" during night or daytime sleep. In conclusion, ritanserin may serve as add-on medication for the treatment of impaired sleep quality in narcoleptic patients, but not as a stimulant or hypnotic type of medication.

The ameliorating effect of the water layer of Fructus Schisandrae on cycloheximide-induced amnesia in rats: interaction with drugs acting at neurotransmitter receptors.

Our previous study indicated that the water layer present in Fructus Schisandra(FS(w)) at 10 and 25 mg kg(-1)significantly counteracted cycloheximide (CXM)-induced amnesia. Therefore, the mechanism of action of the ameliorating effect of FS(w)on CXM-induced amnesia in the passive avoidance task was investigated in rats. The ameliorating effect of FS(w)on CXM-induced amnesia was depressed by scopolamine. The serotonin releaser, p -chloroamphetamine significantly antagonized the ameliorating effect of FS(w)on CXM-induced amnesia. Furthermore, the ameliorating effect was also inhibited by the 5-HT(1A)receptor agonist 8-OH-DPAT, but potentiated by the 5-HT(2)receptor antagonist ritanserin. Finally, the GABA(A)receptor antagonist bicuculline blocked the ameliorating effect of FS(w). These results suggest that the beneficial effect of FS(w)on CXM-induced amnesia is amplified by treatment with serotonergic 5-HT(2)receptor antagonists, but reduced by serotonergic 5-HT(1A)receptor agonists as well as GABA(A)and cholinergic receptor antagonists.

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.

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.

5-HT2 receptor antagonism reduces hyperactivity induced by amphetamine, cocaine, and MK-801 but not D1 agonist C-APB.

The hyperlocomotion induced by the noncompetitive NMDA antagonist MK-801 (0.3 mg/kg SC) in mice was attenuated by the nonselective 5-HT2 antagonist ritanserin (0.12 and 0.25 mg/kg SC) and by the 5-HT2A selective antagonist MDL100907 (0.05 and 0.1 mg/kg SC). SB242084 (0.25-1.0 mg/kg), a selective 5-HT(2C) antagonist, had no effect on MK-801-induced hyperactivity. These same doses of ritanserin and MDL100907 reduced the hyperactivity induced by cocaine (10 mg/ kg). Amphetamine (2.5 mg/kg SC) induced hyperlocomotion that was also attenuated by ritanserin (0.064).25 mg/kg SC). The hyperlocomotion induced by the D1 agonist C-APB (1.0 mg/kg) is not altered by pretreatment with ritanserin or MDL100907. This suggests that compounds that increase locomotor activity via indirectly increasing dopaminergic activity (either by increased release or blockade of reuptake) require the activation of a 5-HT2A receptor. Activity of compounds that act directly at the postsynaptic dopamine receptors such as C-APB is not dependent on such a mechanism. This suggests a selective involvement of 5-HT2A receptors but not 5-HT2c receptors in the mediation of the behavioral effects of compounds that increase synaptic concentration of dopamine but not directly acting agonists. This implies that the 5-HT2A receptors modulate elevation of extracellular dopamine, not the postsynaptic sensitivity of dopamine neurons.

Relationships between midembryonic 5-HT2 agonist and/or antagonist exposure and detour learning by chickens.

The importance of serotonin (5-HT) as both a transmitter and a regulatory signal during development of many species is well established. The availability of 5-HT receptor subtype agonists and antagonists will enable pharmacological dissection of the importance of one or more of the 5-HT receptors for their involvement in the mediation of developmental insults by drugs that are less selective but include actions upon serotonergic function. Such insults include exposure to cocaine or opiate withdrawal, both of which are blocked or attenuated by 5-HT2 antagonists. The 5-HT2 receptor agonist dimethoxyiodophenylaminopropane (DOI), like cocaine, causes vasoconstriction during embryogenesis, herniated umbilici in hatchlings, and altered detour learning by young chickens after injection into eggs at late stages of embryogenesis. The 5-HT2 antagonist ritanserin (RIT) blocks or significantly attenuates these effects. This study describes an effect of DOI on posthatch detour learning when injected earlier during embryogenesis (i.e., on embryonic day 12, E12) which is opposite its effect when injected later (i.e., on E15). Both effects are blocked by an inactive dose of RIT (0.3 mg/kg egg) and by a higher dose of RIT (0.9 mg/kg egg), which itself retards posthatch detour learning following E12 injection. Thus, excessive stimulation or blockade of 5-HT2 receptors around midembryogenesis can cause a similar behavioral teratogenic outcome. The data are discussed in relation to the likelihood that potential use of 5-HT2 antagonists for treating pregnant women and their fetuses who are not at risk is nil.

Behavioral and neuroendocrine assessment of ritanserin exposure in the developing chicken: lack of toxicity at effective doses.

The 5-HT2 antagonist ritanserin (RIT) is undergoing Phase III clinical trials for the treatment of substance abuse disorders. RIT has also shown preclinical therapeutic potential for attenuating or blocking lethal and/or toxic effects of exposure to cocaine or the selective 5-HT2 agonist dimethoxyiodophenyl-aminopropane (DOI) in the developing chicken. To assess the potential toxicity ("side effects") of RIT itself during development, we exposed chicken embryos to 0, 0.1, 0.3, 0.9, or 2.7 mg RIT/kg egg by injecting the drug into eggs with 14-day-old embryos (E14). Voltage generated by spontaneous embryonic activity (motility) was measured on E15 to assess short-term effects of RIT; none were observed. There was no overall effect of these RIT doses on hatchability, though sample sizes were small (n = 13-15 per group). One to 2 weeks after hatching, chicks' acquisition of a detour learning response was tested. There were no observable effects of any RIT dose on detour learning. To assess potential effects of RIT on responsiveness to stress, some chicks were exposed to isolation stress approximately 3 weeks after hatching and killed 15 min later. Blood was assayed for serum corticosterone. There was no effect of any embryonic RIT dose on corticosterone concentrations in nonstressed subjects. Although corticosterone was elevated in all stressed groups, the group exposed to the highest embryonic RIT dose (2.7 mg/kg egg) showed a stress-induced elevation greater than other groups. Thus, except for the highest RIT dose (six to seven times greater than a therapeutically effective dose used in earlier work), embryonic RIT exposure on E14 had no effect on embryonic behavior, hatchability, posthatch learned behavior, and basal serum corticosterone concentrations. At a supraefficacious dose it appears to have modified the responsiveness of the neuroendocrine axis to mild stress.

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.