Involvement of 5-hydroxytryptamine1A receptors in Delta9-tetrahydrocannabinol-induced catalepsy-like immobilization in mice

The present study investigated the involvement of 5-hydroxytryptamine_1A (5-HT_1A) receptors in Δ⁹-tetrahydrocannabinol (THC)-induced catalepsy-like immobilization in mice. THC (10 mg/kg, i.p.) induced catalepsy-like immobilization but had no effect on motor coordination in the rota-rod test. The selective cannabinoid CB₁ receptor antagonist rimonabant (3 mg/kg, i.p.) completely antagonized THC-induced catalepsy-like immobilization. The 5-HT_1A/5-HT₇ receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 0.3 and 1 mg/kg, i.p.) and 5-HT_1A receptor partial agonist buspirone (0.06 and 0.1 mg/kg, i.p.) inhibited this THC-induced catalepsy-like immobilization. Moreover, the selective 5-HT_1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohezane carboxamide dihydrochloride (WAY100635; 0.3 or 1 mg/kg, i.p.) reversed the inhibition of THC-induced catalepsy-like immobilization by 8-OH-DPAT (1 mg/kg) or buspirone (0.06 mg/kg). In contrast, the selective 5-HT₇ receptor antagonist (R)-3-[2-[2-(4-methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulfonyl]phenol hydrochloride (SB269970) had no effect on this inhibitory effect of 8-OH-DPAT. On the other hand, WAY100635 (0.3 and 1 mg/kg, i.p.) enhanced the catalepsy-like immobilization induced by THC (6 mg/kg, i.p.). These findings suggest that the 5-HT_1A receptors are involved in THC-induced catalepsy-like immobilization.     

Delta(9)-tetrahydrocannabinol prolongs the immobility time in the mouse forced swim test: involvement of cannabinoid CB(1) receptor and serotonergic system

In the present study, we investigated the effect of Delta(9)-tetrahydrocannabinol (THC), the principal psychoactive component of marijuana, on immobility time during the forced swim test. THC (2 and 6 mg/kg, i.p.) significantly prolonged the immobility time. In addition, THC at the same doses did not significantly affect locomotor activity in the open-field test. The selective cannabinoid CB(1) receptor antagonist rimonabant (3 mg/kg, i.p.) significantly reduced the enhancement of immobility by THC (6 mg/kg). Similarly, the selective serotonin (5-HT) reuptake inhibitor (SSRI) citalopram (10 mg/kg, i.p.) and 5-HT(1A/7) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.3 mg/kg, i.p.) significantly reduced this THC-induced effect. Moreover, the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide dihydrochloride (WAY100635, 1 mg/kg, i.p.) and the postsynaptic 5-HT(1A) receptor antagonist MM-77 (0.1 mg/kg, i.p.) reversed this reduction effect of 8-OH-DPAT (0.3 mg/kg). In contrast, the selective 5-HT(7) receptor antagonist (R)-3-[2-[2-(4-methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulfonyl]phenol hydrochloride (SB269970) had no effect on this reduction effect of 8-OH-DPAT. WAY100635 (1 mg/kg) also reversed the reduction effect of citalopram (10 mg/kg). These findings suggest that the 5-HT(1A) receptors are involved in THC-induced enhancement of immobility.     

Involvement of 5-hydroxytryptamine(1A) receptors in nicotine-induced tail tremor in rats

Involvement of the serotonergic system in tail tremor induced by repeated administration of nicotine was investigated in rats. Tail tremor induced by nicotine (0.5 mg/kg, s.c.) was suppressed by a 5-HT(1A) receptor antagonist, N-?2-[4-(2-methoxyphenyl)-1-piperazinyl-]ethyl?-N-(2-pyridinyl)cycloh exanecarboxamide trihydrochloride (WAY-100635; 0.3-3 mg/kg, i.p.), but not by a 5-HT(2) receptor antagonist, ketanserin (0.1-0.3 mg/kg, i.p). The 5-HT(1A) receptor agonists, buspirone (1-20 mg/kg, i.p.), gepirone (1-10 mg/kg, i.p.), tandospirone (1-10 mg/kg, i.p.) and (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.01-0.1 mg/kg, s.c.), enhanced the tail tremor. The enhancement of tail tremor by buspirone (10 mg/kg, i.p.) was blocked by WAY-100635 (0.3-3 mg/kg, i.p.). These findings suggest that nicotine-induced tail tremor is mediated by 5-HT(1A) receptors and that 5-HT(1A) receptor antagonists are effective in the treatment of tremor.     

Effects of 8-hydroxy-2-(di-n-propylamino)tetralin, a selective agonist of 5-HT1A receptors, on the cough reflex in rats.

The effects of the agonist of 5-HT1A receptors, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), on the capsaicin-induced cough reflex in rats were studied. I.p. injection of 8-OH-DPAT, at doses of 0.1 and 0.3 mg/kg, significantly decreased the number of coughs in a dose-dependent manner. The antitussive effect of 8-OH-DPAT (0.3 mg/kg) was blocked by prior injection of methysergide (3 mg/kg i.p.) and spiperone (0.3 mg/kg i.p.), whereas ketanserin (3 mg/kg i.p.) had no effect on the antitussive effect of 8-OH-DPAT. The antitussive effects of dihydrocodeine (1 mg/kg i.p.) and dextromethorphan (3 mg/kg i.p.) were also antagonized by methysergide and spiperone. However, these cough-depressant effects were not reduced by ketanserin. These results suggest that the antitussive action of 8-OH-DPAT may be related to the enhancement of the function of 5-HT1A receptors, and that antitussives interact with the 5-HT1A receptors.     

Antipsychotics improve Delta9-tetrahydrocannabinol-induced impairment of the prepulse inhibition of the startle reflex in mice

Recently, cannabinoid receptor agonists have been reported to impair prepulse inhibition (PPI) of the startle reflex. In the current study, we examined the effect of Delta9-tetrahydrocannabinol (THC), the principal psychoactive component of cannabis, on the PPI, and found that THC (10 mg/kg, i.p.) impaired the PPI concomitant with a decrease in the startle response. Antipsychotics such as haloperidol (0.3 mg/kg, i.p.) and risperidone (0.1 mg/kg, i.p.), which are potent dopamine D2 receptor antagonists, and SR141716 (10 mg/kg, i.p.), a CB1 cannabinoid receptor antagonist, reversed these THC-induced PPI deficits. Moreover, THC (10 mg/kg) increased dopamine (DA) release in the nucleus accumbens but not medial prefrontal cortex over a 50-100-min period (time of PPI test) after treatment, and SR141716 (10 mg/kg) reversed this increase in DA release induced by THC. These results suggest that dopaminergic hyperfunction in the nucleus accumbens may be involved in THC-induced PPI deficits.     

Modulation of 8-OH-DPAT-induced hypothermia by imipramine in rats

The effects of imipramine on 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), the 5-hydroxytryptamine (5-HT)(1A)-receptor full agonist, -induced hypothermia was examined in rats. Single administration of imipramine (30 mg/kg, i.p.) attenuated 8-OH-DPAT-induced hypothermia. This effect of imipramine was blocked by the 5-HT(2A)-receptor antagonist ketanserin. 8-OH-DPAT-induced hypothermia was not altered 24 h after repeated administration of imipramine (1 - 10 mg/kg per day) for 14 days. However, 8-OH-DPAT-induced hypothermia was significantly enhanced in repeated imipramine (10 mg/kg per day)-treated rats that received 8-OH-DPAT plus imipramine 24 h after the final imipramine administration for 14 days. The 5-HT(2A)-receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((+/-)-DOI) attenuated the 8-OH-DPAT-induced hypothermia in drug naive rats. The inhibitory effect of (+/-)-DOI (0.3 mg/kg, s.c.) on 8-OH-DPAT-induced hypothermia was attenuated by repeated administration of imipramine (10 mg/kg per day) for 14 days. These findings suggest that enhancement of the 5-HT(1A) receptors by repeated administration of imipramine may be due to reduction of the inhibitory effects from the 5-HT(2A) receptors to the 5-HT(1A) receptors.     

Serotonergic regulation of mRNA expression of Arc, an immediate early gene selectively localized at neuronal dendrites

Arc (activity regulated, cytoskeleton associated protein) is an effector immediate early gene that is selectively localized in the neuronal dendrites. Elevation of brain 5-HT by the combined administration of the monoamine oxidase inhibitor, tranylcypromine (TCP, 5 mg/kg, i.p.), and the 5-HT precursor L-tryptophan (L-TP, 100 mg/kg, i.p.), increased Arc mRNA abundance in the cingulate, orbital, frontal and parietal cortices as well as in the striatum but a reduction was observed in the CA1 region of the hippocampus. The 5-HT releasing agent p-chloroamphetamine (PCA, 5 mg/kg, s.c.) also increased Arc mRNA in the cortical and striatal areas. Depleting brain 5-HT with the tryptophan hydroxylase inhibitor, p-chlorophenylalanine (pCPA, 300 mg/kg, i.p. for two days), on the other hand, significantly attenuated the increase in Arc mRNA induced by tranylcypromine and L-tryptophan (TCP/L-TP). Pretreatment with the 5-HT2 receptor antagonist ketanserin (2 mg/kg, i.p.) significantly attenuated the effect of TCP/L-TP in the cortex but only partially in striatum and did not affect the reduction in the CA1 region. The 5-HT2 agonist DOI (0.2, 1 and 2 mg/kg, i.p.) dose-dependently increased Arc mRNA abundance in cortical areas with a pattern similar to that of TCP/L-TP and PCA. DOI, however, had much weaker effects on Arc mRNA in the striatum and did not have any significant effect in the CA1, CA3 and the dentate gyms (DG) of the hippocampus. Pretreatment with ketanserin completely blocked the effect of DOI on Arc expression. These data suggest that Arc mRNA expression can be induced in the cortex by increases in extracellular 5-HT and that 5-HT2 receptors play a major part in mediating such effects. Additional 5-HT receptors as well as other neurotransmitters may also be involved, particularly in the striatum and in CA1 subfield of the hippocampus. Overall, our data suggest that expression of Arc mRNA is highly responsive to changes in brain 5-HT functions, and may provide a sensitive marker of postsynaptic 5-HT2(2A and 2C) receptor functions.     

Effects of the serotonin 5-HT2A and 5-HT2C receptor ligands on the discriminative stimulus effects of nicotine in rats

The present study tested the hypothesis that serotonergic (5-HT) 5-HT2A or 5-HT2C receptors or their pharmacological stimulation modulated the discriminative stimulus effects of nicotine in male Wistar rats. To this end the selective 5-HT2A receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (M100,907; 0.5-1 mg/kg, i.p.), the functional 5-HT2A receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI; 0.1-1 mg/kg, s.c.), the selective 5-HT2C receptor antagonist 6-chloro-5-methyl-1-{[2-(2-methylpyrid-3-yloxy)pyrid-5-yl]carbamoyl}indoline (SB 242,084; 0.25-1 mg/kg, i.p.) and the 5-HT2C receptor agonists (S)-2-chloro-5-fluoro-indol-1-yl)-1-methylethylamine fumarate (Ro 60-0175; 0.3-1 mg/kg, s.c.) and (7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole (WAY 163,909; 0.75-1.5 mg/kg, i.p.) were used. Additionally, the effects of the selective alpha4beta2 nicotinic acetylcholine receptor subtype agonist 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5-IA; 0.01 mg/kg, s.c.) were investigated. In rats trained to discriminate (-)-nicotine (0.4 mg/kg, s.c.) from saline in a two-lever, water-reinforced fixed ratio 10 task, substitutions were not observed with 5-HT2 receptor ligands (<32% nicotine-lever responding), conversely 5-IA induced a full substitution (100% nicotine-lever responding). In combination studies, fixed doses of M100,907 (0.5-1 mg/kg) or SB 242,084 (0.25-1 mg/kg) did not alter the dose-response curve of nicotine, while DOI (0.3 mg/kg), Ro 60-0175 (1 mg/kg) and WAY 163,909 (1 and 1.5 mg/kg) attenuated the discriminative stimulus effects of nicotine. The decrease in the expression of the discriminative stimulus effects of nicotine produced by DOI was blocked by M100,907 (1 mg/kg), but not by SB 242,084 (1 mg/kg), while that evoked by Ro 60-0175 or WAY 163,909 was blocked by SB 242,084 (1 mg/kg), but not by M100,907 (1 mg/kg). Further studies showed that DOI (0.3 mg/kg) and Ro 60-0175 (1 mg/kg), but not WAY 163,909 (1.5 mg/kg) blocked full substitution of 5-IA (0.01 mg/kg) for nicotine. Our pharmacological analyses indicate that tonic activation of 5-HT2A or 5-HT2C receptors is not required for subjective effects of nicotine, however these receptors appear to have inhibitory influence on nicotine cue, since pharmacological stimulation of either receptor attenuates the discriminative stimulus effects of nicotine.     

The atypical 5-HT2 receptor mediating tachycardia in pithed rats: pharmacological correlation with the 5-HT2A receptor subtype

1. In pithed rats, 5-HT mediates tachycardia both directly (by 5-HT(2) receptors) and indirectly (by a tyramine-like effect). The receptor mediating tachycardia directly has been classified as an 'atypical' 5-HT(2) receptor since it was 'weakly' blocked by ketanserin. Moreover, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT(2) agonist, failed to mimic 5-HT-induced tachycardia. Since 5-HT(2) receptors consist of 5-HT(2A), 5-HT(2B) and 5-HT(2C) subtypes, this study investigated if these subtypes mediate the above response. 2. In pithed rats, intraperitoneally (i.p.) pre-treated with reserpine (5 mg kg(-1)), intravenous (i.v.) administration of 5-HT, 5-methoxytryptamine (5-MeO-T), 1-(3-chlorophenyl) piperazine (mCPP) and 5-carboxamidotryptamine (5-CT) (10, 30, 100 and 300 microg kg(-1) each), produced dose-dependent tachycardic responses. Interestingly, DOI (10 - 1000 microg kg(-1), i.v.) induced only slight, dose-unrelated, tachycardic responses, whilst the 5-HT(2C) agonist, Ro 60-0175 (10 - 1000 microg kg(-1), i.v.), produced a slight tachycardia only at 300 and 1000 microg kg(-1). In contrast, sumatriptan and 1-(m-trifluoromethylphenyl)- piperazine (TFMPP) were inactive. The rank order of potency was: 5-HT > or =5-MeO-T> mCPP > or =5-CT > or =DOI > Ro 60-0175. 3. The tachycardic responses to 5-HT, which remained unaffected after i.v. saline (0.3 and 1 ml kg(-1)) or propranolol (3 mg kg(-1)), were selectively blocked by the 5-HT(2A) antagonists ketanserin (30 and 100 microg kg(-1)) or spiperone (10 and 30 microg kg(-1)) as well as by the non-selective 5-HT(2) antagonists, ritanserin (10 and 30 microg kg(-1)) or mesulergine (100 microg kg(-1)). Remarkably, these responses were unaffected by the antagonists rauwolscine (5-HT(2B)), SB204741 (5-HT(2B/2C)) or Ro 04-6790 (5-ht(6)) (300 and 1000 microg kg(-1) each). 4. These results suggest that the 'atypical' 5-HT(2) receptors mediating tachycardia in reserpinized pithed rats are pharmacologically similar to the 5-HT(2A) receptor subtype.     

Ejaculatory response induced by a 5-HT2 receptor agonist m-CPP in rats: differential roles of 5-HT2 receptor subtypes

It has been reported that systemic administration of m-CPP (1-[3-chlorophenyl] piperazine hydrochloride), a 5-HT(2) receptor agonist, produces a 5-HT(2C) receptor-mediated penile erections and self-grooming in rats. In the present study, we examined the ability of m-CPP to induce ejaculation in rats and determined which 5-HT(2) receptor subtypes may be involved in the m-CPP-induced ejaculation. The ejaculatory response was assessed by weighing the seminal materials accumulated over 30 min. In Experiment 1, systemic administration of m-CPP (0.1-3.0 mg/kg, i.p.) produced a dose-dependent increase in both the incidence of ejaculation and the weight of the seminal materials. The inverted U-shaped dose-response effects of m-CPP on penile erection and genital grooming were also observed, with maximum effects at 0.6 mg/kg. Pretreatment with SB242084 (0.1 and 0.3 mg/kg, i.p.), a selective 5-HT(2C) receptor antagonist, dose-dependently attenuated the ejaculatory response induced by m-CPP (3.0 mg/kg). The proejaculatory effect of m-CPP was also attenuated by ketanserin (0.3 and 1.0 mg/kg, i.p.), a 5-HT(2A) receptor antagonist, whereas SB204741 (0.1 and 0.3 mg/kg, i.p.), a selective 5-HT(2B) receptor antagonist, significantly potentiated the m-CPP-induced ejaculatory response. Penile erection and genital grooming induced by m-CPP (0.3 mg/kg, i.p.) was only blocked by SB242084. In Experiment 2 (termed as corset test), in rats fitted with a corset at the thoracic level to prevent the loss of seminal materials by genital grooming, the proejaculatory effect of m-CPP was more efficiently detected than in the non-fitted animals: the ED(50) value for inducing ejaculation was reduced to less than 50% of the ED(50) in non-fitted animals. In this test, the proejaculatory effect of m-CPP (0.6 mg/kg, i.p.) was completely blocked by SB242084 (0.3 mg/kg, i.p.), whereas ketanserin (0.3 mg/kg, i.p.) or SB204741 (0.3 mg/kg, i.p.) did not affect the m-CPP -induced ejaculation. From these observations, it is suggested that the 5-HT(2) receptor agonist m-CPP at low doses (0.3-1.0 mg/kg) possesses the proejaculatory as well as proerectile effects in rats that are primarily associated with the activation of 5-HT(2C) receptors, and that the activation of 5-HT2B receptors may produce an inhibitory effect on ejaculation induced by a high dose (3.0 mg/kg) of m-CPP. Furthermore, the results of the present study also indicate that the corset test employed in this study may be useful for detecting the proejaculatory effect of the compounds.     

Effects of antagonists of 1A and 2A/2C subtypes of serotonin receptors on the depressive behavior and expression of c-Fos protein in hypothalamus of ovariectomized rats

We have studied the influence of a chronic administration of the 5-HT(2A/2C) receptor antagonist ketanserin (0.1 mg/kg, i.p.) and the 5-HT(1A) receptor antagonist NAN-190 (0.1 mg/kg, i.p.) alone or in combinations with 17beta-estradiol (0.5 mg per animal, i.m.) for 14 days on the depressive behavior and expression of c-Fos protein in the paraventricular nucleus of hypothalamus in adult ovariectomized (OVX) female rats. The depression in rats was modeled by the Porsolt test. The c-Fos protein expression in the paraventricular nucleus of hypothalamus was determined using immunohistochemical techniques. In the Porsolt test, 17beta-estradiol in OVX rats reduced the immobilization time to some extent. Ketanserin alone significantly decreased the immobilization time in OVX rats. The chronic administration of ketanserin in combination with 17beta-estradiol in OVX females potentiated the antidepressant effect of ketanserin. At the same time, ketanserin administration led to a significant decrease in the level of c-Fos protein in the hypothalamus in OVX rats as compared to the intact control. These results are indicative of a substantial interaction between the ovarian hormonal system and the serotoninergic brain system involved the mechanisms of depression.     

Central antinociceptive activity of acetylsalicylic acid is modulated by brain serotonin receptor subtypes

Male Wistar rats were treated with ondansetron (1 and 2 mg/kg s.c.), ketanserin (0.2, 1 and 5 mg/kg s.c.) or NAN-190 (1, 3 and 5 mg/kg i.p.) 15 min before acetylsalicylic acid (ASA, 400 mg/kg i.p.), and 30 min thereafter the pain threshold was evaluated. The antinociceptive activity of ASA in the hot-plate test was variously affected by ondansetron, ketanserin and NAN-190: at the highest dose (2 mg/kg s.c.) ondansetron abolished it while ketanserin (5 mg/kg s.c.) significantly reduced it, and NAN-190 (1-5 mg/kg) did not significantly modify the effect of ASA. Binding experiments indicate that both ondansetron and ketanserin completely prevented the decrease in the maximum number of 5-HT(2) receptors (B(max)) provoked by ASA. These data indicate that the central antinociceptive activity of ASA is modulated in a different manner by serotonin receptor antagonists, and that 5-HT(2) and 5-HT(3) receptors may exert a pivotal role in nociception, alone or in association.     

Characteristics of learning and memory impairment induced by delta9-tetrahydrocannabinol in rats

We investigated the characteristics of delta9-tetrahydrocannabinol (THC)-induced impairment of learning and memory using an 8-arm radial maze task, a water maze, a visual discrimination task with 2 figures and a passive avoidance test in rats. THC (6 mg/kg, i.p.) impaired spatial memory in the standard task of the 8-arm radial maze. THC (4-6 mg/kg, i.p.) selectively impaired working memory in a reference and working memory task of the 8-arm radial maze. Even at a dose of 10 mg/kg, THC did not impair spatial memory in the water maze. In addition, THC at a dose of 6 mg/kg, which had inhibitory effects in the 8-arm radial maze, did not affect performance in the visual discrimination task. These results indicate that at low doses (2-6 mg/kg), THC may not produce visual function abnormalities. THC impaired retrieval (6 mg/kg, i.p.) as well as acquisition (10 mg/kg, i.p.) in the passive avoidance test. The consolidation process was also impaired by i.c.v. injection (100 microg), but not i.p. injection (6-10 mg/kg) of THC. These results suggest that THC-induced impairment of spatial memory is based on the selective impairment of working memory through its effects on acquisition and retrieval processes.     

Aripiprazole inhibits marble-burying behavior via 5-hydroxytryptamine (5-HT)1A receptor-independent mechanisms

Aripiprazole is a first next-generation atypical antipsychotic drug with dopamine system stabilizing, serotonin (5-hydroxytryptamine, 5-HT) 5-HT(1A) receptor partial agonistic, and 5-HT(2A) receptor antagonistic properties. In the present study, we examined the effect of aripiprazole on marble-burying behavior, which has been considered an animal model of obsessive-compulsive disorder, and compared this with the effects of other atypical antipsychotics such as olanzapine and quetiapine. Aripiprazole (1 mg/kg, i.p.) inhibited marble-burying behavior without affecting the locomotor activity in mice. Conversely, olanzapine (3 mg/kg, i.p.) and quetiapine (100 mg/kg, p.o.) showed significant suppression of locomotor activity and impairment of motor coordination at the dose that inhibited marble-burying behavior. On the other hand, a selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane (WAY100635, 3 mg/kg, i.p.) markedly antagonized the inhibition of marble-burying behavior by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 3 mg/kg, i.p.), a selective 5-HT(1A/7) receptor agonist. By contrast, WAY100635 at the same dose had no effect on the inhibition of marble-burying behavior by aripiprazole (1 mg/kg, i.p.). Quinpirole, a dopamine D(2) receptor agonist, showed significant suppression of locomotor activity at the dose that inhibited marble-burying behavior. Conversely, L-741,626, a selective dopamine D(2) receptor antagonist, at a dose of 10 mg/kg inhibited marble-burying behavior without affecting the locomotor activity. On the other hand, ketanserin, a 5-HT(2A) receptor antagonist, had no effect on the marble-burying behavior. These findings suggest that aripiprazole may be a useful drug for the treatment of obsessive-compulsive disorder, and that aripiprazole inhibits the marble-burying behavior via 5-HT(1A) receptor-independent mechanisms.     

Differential involvement of 5-HT(2A) receptors in the discriminative-stimulus effects of cocaine and methamphetamine

Involvement of 5-HT(2A) receptors in the discriminative-stimulus effects of cocaine versus methamphetamine was studied in Sprague Dawley rats (n=10) trained to discriminate 10 mg/kg cocaine, i.p., from saline under a fixed-ratio 10 (FR10) schedule of food presentation. The ability of (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT(2A) receptor agonist, and ketanserin, a 5-HT(2A) receptor antagonist, to either substitute for or block the discriminative-stimulus effects of cocaine, or to shift the cocaine dose-response curve, was evaluated. DOI (0.18-1.0 mg/kg) partially substituted for the training dose of 10 mg/kg cocaine, but only at doses that decreased rates of responding. At the highest dose of DOI tested (1.0 mg/kg), there was about 65% cocaine-appropriate responding. Substitution of DOI for cocaine and DOI-induced decreases in rates of responding were completely reversed by ketanserin (3.0 mg/kg). Ketanserin (3.0 mg/kg) also produced a significant shift to the right of the cocaine dose-response curve and antagonized increases in rates of responding produced by lower doses of cocaine. Ketanserin (1.0-10.0 mg/kg), however, did not block the discriminative-stimulus effects of the training dose of cocaine. When DOI (0.3 mg/kg) was co-administered with different doses of cocaine, there was a slight leftward shift in the cocaine dose-response curve, which was not significant and appeared to reflect simple additive effects of DOI and cocaine. In contrast, the same dose of DOI (0.3 mg/kg) produced a marked and highly significant shift to the left of the methamphetamine (0.18-1.0 mg/kg) dose-response curve in the same subjects and the effects of DOI and methamphetamine were clearly more than additive. The present findings provide new evidence that there is some serotonergic modulation of cocaine's discriminative-stimulus actions, which appears to involve stimulation of 5-HT(2A) receptors. However, involvement of 5-HT(2A) receptor activity in the discriminative-stimulus actions of cocaine appears to be less pronounced than in similar actions of methamphetamine.     

Bromocriptine-induced hypothermia in Balb/C mice: its possible mechanism of action.

1. Administration of bromocriptine (0.1-2.5 mg/kg, i.p.) to mice produced hypothermia. 2. Pretreatment with the alpha 1-adrenoceptor blocker, prazosin (2.0 mg/kg, i.p.) or the alpha 2-adrenoceptor antagonist yohimbine (2.5 mg/kg, i.p.) had no effect on this response. 3. The inhibitor of catecholamine synthesis, alpha-methyl-p-tyrosine, and the muscarinic antagonist, atropine (10 mg/kg, i.p.) failed to alter the hypothermia. 4. Pretreatment with the dopamine (DA) receptor antagonists haloperidol (0.02 mg/kg, i.p.) or cis-flupenthixol (0.01 mg/kg, i.p.) completely blocked this response while trans-flupenthixol (0.05 mg/kg, i.p.) was inactive. 5. Depletion of 5-HT in the brain by p-chlorophenylalanine reduced the hypothermic response. 6. Similarly, pretreatment with the serotonergic (5-HT) receptor blocker ketanserin (1 mg/kg, i.p.) attenuated the hypothermia and at a dose of 2 mg/kg (i.p.) it completely blocked the hypothermic response. 7. Methysergide (5 mg/kg, i.p.) was also effective in antagonizing the hypothermia. 8. It was concluded that both DA and 5-HT mechanisms are involved in bromocriptine-induced hypothermia in mice.     

Effects of the 5-HT1C/5-5-HT2 receptor agonists DOI and alpha-methyl-5-HT on plasma glucose and insulin levels in the rat

Administration of the 5-HT1C/5-HT2 receptor agonist 1-(2,5-dimethoxy-4- iodophenyl)-2-aminopropane (DOI, 0.125-2.0 mg/kg i.v.) triggered dose-dependent increases in plasma glucose; plasma insulin levels remained unchanged. Pretreatment with the 5-HT1C/5-HT2 receptor antagonists LY 53857, ritanserin, or the mixed 5-HT2/alpha 1-adrenoceptor antagonist ketanserin either diminished or prevented the hyperglycemic effect of DOI (0.5 mg/kg). Administration of the mixed 5-HT1C receptor agonists/5-HT2 receptor antagonists 1-(3-chlorophenyl)-piperazine (mCPP) or 1-(3-trifluoromethyl)phenyl)piperazine level (TFMPP) did not affect plasma glucose levels. However, pretreatment with mCPP or TFMPP decreased DOI-induced hyperglycemia in a dose-dependent manner. The alpha 2-adrenoceptor antagonist idazoxan and the ganglionic blocker hexamethonium both decreased DOI-induced hyperglycemia, Whilst the alpha 1-adrenoceptor antagonist prazosin amplified the rise in plasma glucose elicited by DOI. The peripherally acting 5-HT1C/5-HT2 receptor agonist alpha-methyl-5-HT (0.5-1.0 mg/kg i.v.) triggered a rise in plasma glucose levels that was associated with an increase in plasma insulin levels. Pretreatment with LY 53857 diminished alpha-methyl-5-HT-induced hyperglycemia. These data indicate that 5-HT2 receptors, but not 5-HT1C receptors, and catecholaminergic systems, mediate DOI-induced hyperglycemia. Moreover, it is suggested that the inhibition of insulin release by DOI is centrally mediated, and that activation of peripheral 5-HT2 receptors may affect glycemia.     

Induction of purposeless chewing behaviour in rats by 5-HT agonist drugs

The 5-HT agonist m-chlorophenylpiperazine (m-CPP; 1-16 mg/kg i.p. or s.c.), trifluoromethylphenylpiperazine (TFMPP; 2-16 mg/kg i.p.) and quipazine (2.5-20 mg/kg i.p.) increased purposeless chewing behaviour in rats. However, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.025-4 mg/kg s.c.) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT; 0.25-8 mg/kg s.c.) were without effect on chewing behaviour. Chewing behaviour induced by m-CPP (6 mg/kg s.c.) was antagonised by pretreatment with the 5-HT antagonists methiothepin and mianserin, but not by ketanserin or spiperone, or ICS 205-930. m-CPP (6 mg/kg s.c.)-induced chewing behaviour was also antagonised by pretreatment with (-)-propranolol (20 mg/kg). Pretreatment with the anticholinergic drugs benzhexol (2.5 mg/kg), and scopolamine (1 mg/kg) antagonised m-CPP (6 mg/kg s.c.)-induced chewing behaviour, but methylscopolamine (1 mg/kg) had no effect. These data support the role of 5-HT receptors in the mediation of purposeless chewing behaviour and suggest an interaction between brain 5-HT and acetylcholine systems.     

The effects of the peptide-coupling agent, EEDQ, on 5-HT2A receptor binding and function in rat frontal cortex.

This ex vivo study in rat frontal cortex determined the influence of 5-HT receptor agonists and antagonists on EEDQ-induced depletion of 5-HT2A binding sites and reduction in their functional coupling to phospholipid hydrolysis. Twenty-four hours after EEDQ (6 mg/kg) administration a marked reduction (66%) of cortical 5-HT2A binding sites with no change in binding affinity was observed. The 5HT2A antagonists ritanserin (1 mg/kg), ketanserin (1 and 5 mg/kg), metergoline (3 mg/kg) or the 5HT2A agonist, DOI (3 and 10 mg/kg) also significantly reduced (by 15-44%) these binding sites 24 h after injection. Thirty minute pretreatment with ritanserin, ketanserin, metergoline or DOI (at the doses above) afforded 49-65% protection against the loss of 5-HT2A binding sites induced by EEDQ (6 mg/kg). DOI (10 mg/kg) pretreatment (-24 h) decreased by 26% the accumulation of [3H]inositol phosphates (IPs) evoked by 5-HT (100 microM), but did not affect that produced by DOI (100 microM). Ketanserin (5 mg/kg, -24 h) decreased 5-HT- and DOI-induced IP formation by 65% and 53%, respectively. The EEDQ (6 mg/kg, -24 h)-evoked reductions (-50%) of 5-HT- and DOI-induced IP formation were not altered by DOI (10 mg/kg) or ketanserin (5 mg/kg) given 30 min before EEDQ. G-protein-stimulated IP accumulation was unaffected by EEDQ (6 mg/kg). Overall, EEDQ reduces 5-HT2A binding sites and function in rat frontal cortex, whereas its effects on binding were attenuated by various 5-HT receptor antagonists and agonists, its effects on function was unaltered by these drugs.     

Perospirone, a novel antipsychotic drug, inhibits marble-burying behavior via 5-HT1A receptor in mice: implications for obsessive-compulsive disorder

Perospirone is a novel atypical antipsychotic drug with dopamine (DA) D(2)- and serotonin (5-hydroxytryptamine, 5-HT) 5-HT(2A)-receptor antagonist, and 5-HT(1A)-receptor agonist properties. In the present study, we examined the effect of perospirone on marble-burying behavior, which has been considered an animal model of obsessive-compulsive disorder (OCD), compared with the effects of other antipsychotics such as haloperidol and risperidone. Perospirone at a dose of 10 mg/kg (p.o.) inhibited marble-burying behavior without affecting the locomotor activity in mice. On the other hand, haloperidol (0.1 mg/kg, i.p.) and risperidone (1 mg/kg, p.o.) showed significant suppression of locomotor activity at the dose that inhibited marble-burying behavior. Furthermore, the inhibition of marble-burying behavior by perospirone was antagonized by WAY100135 (10 mg/kg, i.p.), a selective 5-HT(1A)-receptor antagonist. WAY100135 at the same dose also antagonized the inhibition of marble-burying behavior by 8-OH-DPAT (3 mg/kg, i.p.), a selective 5-HT(1A)-receptor agonist. These findings suggest that perospirone may exhibit anti-OCD activity in clinical use and that 5-HT(1A)-receptor agonistic activity may be involved in the inhibition of marble-burying behavior by perospirone.