Naltrexone, serotonin receptor subtype antagonists, and glucoprivic intake: 2. Insulin.

Opiate antagonist inhibition of deprivation-induced intake and 2-deoxy-D-glucose (2DG) hyperphagia is significantly enhanced by the 5-hydroxytryptamine3 (5-HT3) antagonist, ICS-205,930. Interactions between opiate antagonists and either 5-HT or 5-HT2 antagonists produced smaller effects. The present study evaluated whether insulin (5 U/kg) hyperphagia was affected by methysergide (0.5-5 mg/kg), ritanserin (0.25-2.5 mg/kg), and ICS-205,930 (0.5-5 mg/kg) alone or in combination with naltrexone (2.5-10 mg/kg). Whereas ICS-205,930 stimulated insulin hyperphagia across the 6-h time course, ritanserin and, to a lesser degree, methysergide reduced insulin hyperphagia. Naltrexone marginally (19-33%) reduced insulin hyperphagia. Pairing naltrexone with either ICS-205,930 or ritanserin significantly suppressed insulin hyperphagia after 2 h. Pairing naltrexone with each of the serotonin antagonists significantly enhanced insulin hyperphagia after 4 and 6 h. These data suggest that 5-HT2 and 5-HT3 receptor subtypes interact with opioid systems to modulate insulin hyperphagia. Given that central insulin reduces food intake and body weight, the interaction between serotonergic and opioid systems may occur peripherally.     

2-Deoxy-D-glucose antinociception and serotonin receptor subtype antagonists: test-specific effects in rats.

The antinociceptive actions of 2-deoxy-D-glucose (2-DG) are mediated in part by endogenous opioid, dopaminergic, cholinergic, histaminergic, and neurohormonal influences. Although 2-DG antinociception was not affected by tryptophan hydroxylase inhibition, a possible serotonergic role in 2-DG antinociception was investigated because of the existence of serotonin [5-hydroxytryptamine (5-HT)] receptor subtypes. The present study examined the effects of general (methysergide: 5 and 10 mg/kg), 5-HT2 (ritanserin: 2.5 mg/kg), and 5-HT3 (ICS-205,930: 0.25-5 mg/kg) receptor subtype antagonists upon 2-DG antinociception on the tail-flick and jump tests in rats. On the tail-flick test, 2-DG (450 mg/kg) antinociception was significantly reduced by all ICS-205,930 doses (48-58%) but unaffected by either methysergide (22-29% reduction) or ritanserin (6% reduction). In contrast, 2-DG antinociception on the jump test was significantly potentiated across the 120-min time course and across the 2-DG dose-response curve (100-650 mg/kg) by methysergide, ritanserin, and ICS-205,930 pretreatment. Each of the three antagonists produced significant leftward shifts in the peak and total 2-DG dose-response curve for the jump test. These data suggest different sites of action for 2-DG antinociception as a function of the pain test employed and a differential modulation by serotonin receptor subtypes at those sites.     

Naloxone and serotonin receptor subtype antagonists: interactive effects upon deprivation-induced intake

Whereas opiate receptor antagonists generally act to inhibit food intake under a variety of physiological conditions in rats, agonists of some serotonin (5-HT) receptor subtypes appear to stimulate intake, and others appear to inhibit intake. The present study evaluated the effects of the general 5-HT receptor antagonist, methysergide (1-5 mg/kg), the 5-HT2 receptor antagonists, ketanserin (1-2.5 mg/kg) and ritanserin (1-2.5 mg/kg), and the 5-HT3 receptor antagonist, ICS 205930 (1-5 mg/kg) upon deprivation (24 h)-induced intake themselves, and upon the hypophagic properties of the general opiate receptor antagonist, naloxone (1-5 mg/kg). Whereas the high doses of methysergide (0.5-4 h, 34%) and ketanserin (0.5 h, 28%) significantly decreased deprivation-induced intake themselves, ritanserin and ICS 205930 were without effect. Naloxone produced dose-dependent reductions in deprivation-induced intake (24-45%). Methysergide (1 mg/kg) significantly potentiated naloxone (5 mg/kg) hypophagia after 0.5 h. Significant potentiations of hypophagia occurred following pairing the 1 mg/kg ketanserin dose with the 1 and 5 mg/kg naloxone doses at 2 and 4 h respectively, and pairing the 2.5 mg/kg ketanserin and 1 mg/kg naloxone doses at 0.5 and 2 h. Whereas the 1 mg/kg dose of ritanserin eliminated naloxone (1 mg/kg) hypophagia over a 2-h time course, ritanserin failed to exert further effects in other dose conditions. The differences between ketanserin and ritanserin in their effects upon deprivation-induced feeding and naloxone hypophagia suggest that the former's antagonistic actions upon alpha-adrenergic receptors may be responsible for its effects.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Peripheral 5-carboxamidotryptamine (5-CT) elicits drinking by stimulating 5-HT1-like serotonergic receptors in rats.

Subcutaneous administration of the prototypical 5-HT1-like agonist, 5-carboxamidotryptamine (5-CT), increased 2-h water intake by nondeprived rats (ED50 = 0.04 mumol/kg). The 5-HT1 agonists 8-hydroxy-2-(di-N-propylamino)-tetralin (8-OH-DPAT, 0.04-0.32 mumol/kg) and RU 24969 (0.16 mumol/kg) did not produce drinking. The dipsogenic effect of 5-CT (0.08 mumol/kg) was prevented by the 5-HT1/2 antagonist, methysergide (ID50 = 4 mumol/kg), but not by 16 mumol/kg of the 5-HT2 antagonist, ketanserin; the 5-HT21C antagonist, mianserin; or the 5-HT3 antagonist, MDL 72222, 5-CT also increased drinking and reduced food intake when food-deprived rats were given 2-h access to mash. Methysergide (16 mumol/kg) inhibited both actions of 5-CT but an equimolar dose of the 5-HT1/beta adrenergic antagonist, (-)-propranolol, blocked only the drinking. The 5-HT21C antagonist, ritanserin (16 mumol/kg), altered neither ingestive action of 5-CT although, by itself, ritanserin increased mash intake. The results suggest that activating a subtype of peripheral 5-HT1-like receptor stimulates drinking in rats. This receptor is unlike either the 5-HT1A or the 5-HT1C sites found in the brain. Furthermore, the dipsogenic and anorectic actions of 5-CT occur independently.     

Behavioural studies on WAY100289, a novel 5-HT3 receptor antagonist, in two animal models of anxiety.

The novel 5-HT3 receptor antagonist, WAY100289, was examined in two animal models of anxiety: the mouse two-compartment light: dark box, and the rat potentiated acoustic startle paradigm. The activity of WAY100289 in the light: dark box model was also compared with that of the selective 5-HT3 receptor antagonists ondansetron, zacopride, ICS-205,930 and quaternary ICS-205,930 (QICS). WAY100289 mimicked the activity profile of benzodiazepine positive controls in the mouse light: dark box, i.e. WAY100289 markedly and significantly increased the exploratory activity of mice in the more aversive light compartment, at doses of 0.01-1.0 mg/kg s.c. and 0.1-10.0 mg/kg p.o. Zacopride and ondansetron induced comparable effects at doses of 0.001-1.0 mg/kg s.c. ICS-205,930 displayed a markedly biphasic dose-response relationship; being active at 0.01 mg/kg s.c., but not at higher or lower doses. QICS was not active in the light: dark box up to a dose of 10 mg/kg s.c., suggesting that the compound does not enter the brain readily. WAY100289 was also active in the rat potentiated acoustic startle model, significantly attenuating the potentiated startle response at doses of 0.03 and 0.3 mg/kg s.c. The activity profile of WAY100289 in this model resembled that of ondansetron. These data strongly suggest that WAY100289 may possess anxiolytic properties in the clinic.     

Repeated administration of low doses of cocaine enhances the sensitivity of 5-HT2 receptor function.

The acute and chronic effects of cocaine were evaluated on the 5-hydroxytryptamine (5-HT)-receptor 5-HT2 mediated behavioral function, the head-twitch response (HTR), in mice. In a recent study, we reported that the (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI)-induced HTR was dose dependently reduced by cocaine via indirect stimulation of serotonergic 5-HT1A and adrenergic alpha 2 receptors. In the present investigation, the HTR was evoked by the nonselective 5-HT agonist 5-methoxy-N,N-dimethyltryptamine hydrogen oxolate (5-MeO-DMT). Cocaine by itself failed to produce HTR but dose dependently inhibited the 5-MeO-DMT-induced behavior. Cocaine's effects were not due to 5-HT3 antagonism since acute administration of the more potent 5-HT3 antagonist (ICS-205,930) failed to produce or modify the 5-MeO-DMT-induced behavior. During withdrawal from chronic cocaine treatment (5-20 mg/kg), 5-MeO-DMT-induced HTR was enhanced. Depending upon the cocaine dose used, the induced supersensitivity persisted up to 172 h following cessation of cocaine treatment. The mechanisms of cocaine-induced supersensitivity were further investigated using the more selective 5-HT2 agonist DOI. Withdrawal from a low-dose (0.03-1.25 mg/kg) chronic cocaine treatment caused the DOI-induced HTR to increase, whereas withdrawal from a 5- and 10-mg/kg cocaine regimen had no significant effect. The maximal effect persisted up to 36 h following termination of cocaine treatment. Relative to vehicle-exposed controls, withdrawal from cocaine treatment enhanced the inhibitory potency of the 5-HT1A agonist (+-)-8-hydroxy-2-(di-n-propylamino)tetralin HBr (8-OH-DPAT) on DOI-induced HTR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of 5-HT2 receptor antagonist on cycloheximide-induced amnesia in mice

A role played by serotonergic neuronal system in cycloheximide (CXM)-induced amnesia was studied in mice using a step-down passive avoidance task. CXM (30 mg/kg SC) given immediately after training caused impairment of memory. Nonselective serotonin (5-HT) antagonist methysergide and selective 5-HT2 antagonist ritanserin significantly attenuated impairment of memory caused by CXM. 5-HT1 antagonist (+/-)-pindolol had no effect on CXM-induced amnesia. The antiamnesic effect of ritanserin on CXM-induced amnesia was antagonized by 5-HT (ICV), but not by nonselective 5-HT agonist 5-methoxy-N,N-dimethyltryptamine and 5-HT1A selective agonist 8-hydroxy-2-(di-n-propylamino)tetralin at the dose level which did not cause the memory disruption. Scopolamine antagonized the antiamnesic effects of methysergide and ritanserin on CXM-induced amnesia. These results suggest that 5-HT2 receptors and cholinergic neuronal system may play an important role in memory formation.     

Evidence for the involvement of 5-HT1A receptors in the anticonflict effect of ipsapirone in rats.

The anticonflict activity of ipsapirone, a non-benzodiazepine anxiolytic drug, with high affinity for 5-hydroxytryptamine1A (5-HT1A) receptors, was studied in the drinking conflict test in the rat. The drug, administered in doses 1.25-20 mg/kg increased the number of punished licks, with the maximum effect observed after doses of 5-20 mg/kg of ipsapirone. The anticonflict effect of ipsapirone (5 mg/kg) was dose-dependently antagonized by the 5-HT1A receptor, alpha 1-adrenoceptor and dopamine receptor antagonist, NAN-190 (0.25-1 mg/kg) and by the beta-adrenoceptor blocker, SDZ 21009, which also has a high affinity for 5-HT1A and 5-HT1B receptors (2-8 mg/kg). On the other hand, the non-selective 5-HT receptor antagonist, metergoline (2 and 4 mg/kg), the 5-HT2/5-HT1C receptor antagonist, ritanserin (0.25 and 0.5 mg/kg), the selective alpha 1-adrenoceptor blocker, prazosin (0.25-0.5 mg/kg) and the beta-blockers, betaxolol (8 mg/kg) and ICI 118 551 (8 mg/kg), which have no affinity for 5-HT receptors, did not affect the anticonflict action of ipsapirone. The effect of ipsapirone was also not modified in animals with lesions of 5-HT neurones, produced by p-chloroamphetamine (PCA--2 x 10 mg/kg). These results suggest that the anticonflict effect of ipsapirone in the Vogel test, results from its interaction with 5-HT1A receptors, which are probably located postsynaptically.     

Influence of catecholaminergic and serotonergic receptor antagonists on the hyperglycaemic response to the neuroglucopaenic agent, 2-deoxy-D-glucose.

The intravenous administration of 2-deoxy-D-glucose (2-DG) to conscious catheterised rats dose-dependently increased the levels of glucose in plasma throughout the analysis (60 min); the levels of insulin in plasma remained unchanged, except for an early significant decrease in rats treated with the largest dose (1 g/kg). Pretreatment (10 min beforehand) with the beta 2-adrenoceptor antagonist, ICI 118,551 (3 mg/kg) or the alpha 2-adrenoceptor antagonist, idazoxan (1 mg/kg) decreased the rise in levels of glucose in plasma elicited by 2-DG (250 mg/kg). Conversely, the alpha 1-adrenoceptor antagonist, prazosin (1 mg/kg) or the dopaminergic receptor blocker, haloperidol (0.5 mg/kg) amplified the hyperglycaemic response to 2-DG. Previous administration of either the 5-HT1A/5-HT2 receptor antagonist, spiperone (3 mg/kg), the 5-HT1/5-HT2 receptor antagonist, methysergide (1 mg/kg), the 5-HT1C/5-HT2 receptor antagonist, ritanserin (1 mg/kg) or the 5-HT3 receptor antagonist, ICS 205.930 (0.1 mg/kg) did not affect 2-DG-induced hyperglycaemia. On the other hand, the mixed 5-HT1A/5-HT1B/beta-adrenoceptor antagonist, (-)-propranolol (5 mg/kg) and the 5-HT1/5-HT2 receptor antagonist, methiotepin (1 mg/kg), respectively, diminished and amplified the hyperglycaemia elicited by 2-DG. Lastly, in rats pretreated with prazosin (1 mg/kg, 30 min beforehand), an additional pretreatment (10 min beforehand) with prazosin or methiotepin (both at 1 mg/kg) did not further amplify the hyperglycaemic response to 2-DG. These results indicate that 2-DG-induced hyperglycaemia is mediated by alpha 2- and beta 2-adrenoceptors and amplified by alpha 1-adrenoceptor blockade. Conversely, neither 5-HT1, 5-HT2 nor 5-HT3 receptors played a role in the hyperglycaemic response to 2-DG.     

Reversal of delta 9-THC hyperphagia by SR141716 and naloxone but not dexfenfluramine.

Presatiated adult male Lister hooded rats received oral administration of the exogenous cannabinoid Delta-9-tetrahydrocannabinol (Delta(9)-THC; 1.0 mg/kg) in combination with subcutaneous injection of either the cannabinoid CB1 antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR141716; 0, 0.05, 0.1, 0.5 or 1.0 mg/kg), the CB2 antagonist N-[(1S)-endo-1,3,3-trimethyl bicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; 0, 0.05, 0.1, 0.5 or 1.0 mg/kg), the general opioid antagonist naloxone (0.1, 0.5, 1.0 or 5.0 mg/kg) or the 5-HT agonist dexfenfluramine (0.05, 0.1, 0.5, 1.0 or 5.0 mg/kg). Food (chow) intake was measured over 2 h from the onset of the dark period. Delta(9)-THC induced significant hyperphagia, which was attenuated by subanorectic doses of SR141716 and naloxone. Neither SR144528 nor dexfenfluramine affected Delta(9)-THC-induced feeding. These data confirm mediation of Delta(9)-THC hyperphagia by central-type CB1 receptors, and support a functional relationship between cannabinoid and opioid systems in relation to appetite regulation. Stimulation of CB1 receptors may promote feeding by actions on food reward rather than by inhibition of serotonergic satiety mechanisms.     

Glycine receptor beta subunits play a critical role in potentiation of glycine responses by ICS-205,930

The sensitivity of various types of recombinant glycine receptors (GlyRs) to ICS-205,930 was studied by fast perfusion in Xenopus laevis oocytes. This compound has previously been shown to potentiate glycine responses in rat spinal neurons between 10 nM and 1 microM, independently of its 5-HT(3) antagonist properties. In contrast, submicromolar concentrations of ICS-205,930 failed to affect responses of homomeric GlyRs formed from human alpha1 or alpha2 subunits, and micromolar concentrations (1-20 microM) acted differentially on the two types of homomeric receptors, potentiating the responses to glycine (10-20 microM) of alpha1 homomeric GlyRs and inhibiting the responses of alpha2 homomeric GlyRs. GlyRs beta subunits markedly influenced the modulations induced by ICS-205,930. In oocytes expressing alpha1/beta or alpha2/beta heteromeric GlyRs, low concentrations of ICS-205,930 (20 nM-1 microM) induced a potentiation of glycine responses that was counteracted by an inhibitory effect at higher concentrations. Thus, GlyRs beta subunits reduce by 2 orders of magnitude the concentration range potentiating alpha1-containing GlyRs and are required for potentiation of alpha2-containing GlyRs. These results reveal a new high-affinity potentiating site on GlyRs, to which beta subunits participate. The difference in ICS sensitivity between alpha1 and alpha2 GlyRs cannot be explained by their difference in TM2 segment and extracellular domains partly conserved between glycine and 5-HT(3) receptors are probably involved in the interaction of some 5-HT(3) antagonists with GlyRs.     

Studies on the role of 5-HT receptors in satiation and the effect of d-fenfluramine in the runway test

d-Fenfluranine has previously been shown to reduce food-rewarded runway behaviour in the rat, an effect thought to be mediated through activation of central 5-HT pathways. We now examined in more detail the mechanism by which d-fenfluramine reduces runway performance and food intake in the 15-trial runway test. The non-selective 5-HT receptor antagonist, metergoline (1.0 mg/kg), significantly antagonised the effect of d-fenfluramine (2.5 mg/kg) in the runway test. In contrast, neither ritanserin, the potent 5-HT2 and 5-HT1C receptor antagonist (0.5 mg/kg), nor the peripheral 5-HT receptor antagonist, xylamidine (3.0 mg/kg), attenuated the effect of d-fenfluramine in this test situation. Metergoline, but not ritanserin or xylamidine significantly increased runway performance when administered alone. These data indicate that d-fenfluramine reduces runway performance and food intake through activation of 5-HT1 receptors. In addition, blockade of 5-HT1 receptors can attenuate the development of satiation normally observed under control conditions in the runway test.     

Serotonergic and histaminergic mechanisms involved in intralipid drinking?

Some newer antipsychotic agents are associated with weight gain in humans and a hyperphagic response to intralipid solutions in rodents. To examine the possible contribution of serotonin (5-HT) and histamine (H) receptor blockade in antipsychotic-associated hyperphagia, rats were trained to drink a palatable, high-calorie fat emulsion (10% intralipid) during 30-min sessions and were tested following pretreatment with mepyramine (H1 receptor antagonist), metergoline (5-HT(1/2) receptor antagonist), cyproheptadine (H1 and 5-HT(2A/2B/2C) and muscarinic receptor antagonist), SB 242084 (5-HT2C receptor antagonist) and an SB 242084-mepyramine combination. Total intake and ingestive behaviour microstructure were measured. Mepyramine (10 mg/kg) reduced intake, as did metergoline (3.0 mg/kg). Cyproheptadine (0.1-1.0 mg/kg) increased intake and microstructural analysis suggests that this was due to increased numbers of clusters of licking. SB 242084 (3 mg/kg) reduced intake, either when administered alone, or in combination with mepyramine (1 mg/kg). In conclusion, simple antagonism of either H1 (mepyramine) or 5-HT(1/2) receptors (metergoline) alone was not sufficient to increase intake. Furthermore, combined blockade of H1 and 5-HT2C receptors (SB 242084 and mepyramine) was also insufficient to produce hyperphagia. Conversely, simultaneous blockade of H1, 5-HT(2A/2C) and muscarinic receptors (cyproheptadine) led to a substantial hyperphagia and pattern of ingestive behaviour that was similar to that previously observed with some newer antipsychotic agents.     

Discriminative stimulus properties of the atypical antipsychotic drug clozapine in rats trained to discriminate 1.25 mg/kg clozapine vs. 5.0 mg/kg clozapine vs. vehicle

Clozapine, the prototype for atypical antipsychotic drugs, is used in the drug discrimination paradigm as a model for screening atypical from typical antipsychotic drugs. Previous drug discrimination studies in rats have shown that a 1.25 mg/kg clozapine training dose provides full stimulus generalization (i.e.) >or=80% condition-appropriate responding) to most atypical antipsychotic drugs, although a 5.0 mg/kg clozapine training dose appears necessary to provide stimulus generalization to other atypical antipsychotic drugs. The present study sought to characterize the pharmacological mechanisms that mediate these clozapine training doses. In rats trained to discriminate 1.25 vs. 5.0 mg/kg clozapine vs. vehicle in a three-choice drug discrimination task, various receptor-selective compounds were tested for stimulus generalization. The antidepressant mianserin was also tested. Full stimulus generalization from the 1.25 mg/kg clozapine training dose occurred only to mianserin (98.8%). Partial substitution (i.e. >or=60% and <80% condition-appropriate responding) to the 5.0 mg/kg clozapine training dose occurred for the muscarinic receptor antagonist scopolamine. The combined total percentage of responding on the 1.25 and 5.0 mg/kg clozapine levers, however, was well above the full substitution criteria at the 0.25, 0.5, and 1.0 mg/kg scopolamine doses. The M1 agonist N-desmethylclozapine, the nicotinic antagonist mecamylamine, the D1 antagonist SCH 23390, the D4 antagonist LU 38-012, the 5-HT1A agonist (+)-8-OH-DPAT, the 5-HT1A antagonist WAY 100 635, the 5-HT2A/2B/2C antagonist ritanserin, the 5-HT6 antagonist RO4368554, the alpha1 antagonist prazosin, the alpha2 antagonist yohimbine, and the histamine H1 antagonist pyrilamine all failed to substitute for either the 1.25 or the 5.0 mg/kg clozapine training doses. These results are consistent with previous evidence that antidepressant drugs have a tendency to substitute for clozapine and that muscarinic receptor antagonism may mediate the discriminative stimulus properties of 5.0 mg/kg clozapine. The lack of stimulus generalization from either clozapine training dose to other receptor-selective compounds, however, fails to explain how this model screens atypical from typical antipsychotic drugs and suggests that the discriminative stimulus properties of clozapine consist of a compound cue.     

Effects of 5-HT3 antagonists on fixed-interval behavior in rats.

The effects of 5-hydroxytryptamine3 (5-HT3) antagonists were studied in rats responding under a fixed-interval (FI) schedule of food presentation. BRL 43694, GR 38032F, ICS-205,930 and zacopride had no effect on FI responding up to 10.0 mg/kg IP. Response rate decreases were observed only at high doses (30.0 or 56.0 mg/kg); rate increases were not observed. In comparison, caffeine (1.0-10.0 mg/kg) and cocaine (3.0-18.0 mg/kg) increased and lorazepam (0.3 mg/kg) decreased FI responding. The effects of caffeine, cocaine, and lorazepam were unchanged when coadministered with the 5-HT3 antagonists. The results show that 5-HT3 antagonists, when given alone or with other CNS-active drugs, have little effect on FI responding of rats.     

Behavioural evidence for a functional interaction between central 5-HT2 and 5-HT1A receptors.

1. The possibility of 5-HT2 receptor modulation of central 5-HT1A receptor function has been examined using the 5-hydroxytryptamine (5-HT) behavioural syndrome induced by 5-HT1A receptor active drugs in rats. 2. The 5-HT2/5-HTIC antagonist ritanserin (0.1-2 mg kg-1) increased the 5-HT behavioural syndrome induced by submaximally effective doses of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and gepirone. 3. Pretreatment with the 5-HT2/5-HT1C antagonist ICI 170,809 (0.25-5 mg kg-1) also enhanced the behavioural syndrome induced by 8-OH-DPAT or 5-MeODMT. 4. The 5-HT2/alpha 1-adrenoceptor antagonist ketanserin in a low dose (0.25 mg kg-1) significantly increased the 5-HT behavioural syndrome induced by 8-OH-DPAT or 5-MeODMT, while in a higher dose (2.5 mg kg-1) this drug decreased the response. Experiments with prazosin indicate that the higher dose of ketanserin might reduce the 5-HT behavioural syndrome through blockade of alpha 1-adrenoceptors. 5. Ritanserin and ICI 170,809 had no effect on apomorphine-induced stereotypy or hyperactivity, indicating that these drugs do not produce non-specific behavioural activation. 6. Ritanserin and ICI 170,809 inhibited quipazine-induced wet dog shakes at doses similar to those enhancing the 5-HT behavioural syndrome. 7. We suggest that ritanserin, ICI 170,809 and ketanserin enhance 5-HT1A agonist-induced behaviour through blockade of an inhibitory 5-HT2 receptor regulating or coupled to 5-HT1A receptor-mediated function.     

Potentiation of chloride responses to glycine by three 5-HT3 antagonists in rat spinal neurones.

1. Modulations of Cl- responses to glycine by 5-hydroxytryptamine ligands were studied in cultured spinal neurones, by the whole-cell recording technique. 2. Three 5-HT3 antagonists were found to potentiate reversibly responses to low concentrations of glycine. Potentiations were induced by micromolar concentrations of LY-278,584 (1-10 microM) and by concentrations of MDL-72222 or ICS-205,930 between 10 nM and 1 microM. 3. Potentiations were observed over the whole voltage range without any change in the reversal potential of the glycine responses and without affecting the resting conductance. 4. The degree of potentiation was variable among cells. It increased with the concentration of the modulator, but only up to 100 nM for MDL-72222 and ICS-205,930. 5. The potentiation appeared to result from an increase in the affinity for glycine of glycine receptors. 6. Neither the blockade of glycine uptake by Na+ removal, nor the excision of membrane patches prevented the potentiation. 7. At high concentrations (10 microM), both MDL-72222 and ICS-205,930 had, in contrast, a blocking effect on glycine responses. 8. Potentiation by LY-278,584 and a dose-dependent modulation by MDL-72222 were also observed for taurine responses. 9. The effects on glycine responses of various ligands of 5-HT3 receptors (including agonists) are discussed. The ability of LY-278,584, MDL-72222 and ICS-205,930 to potentiate glycine responses appears to be independent of their known 5-HT3 receptor antagonist properties. It would be interesting to look for chemically related drugs that would be specific potentiators of glycine responses.     

On the mechanism of tolerance to morphine-induced Straub tail reaction in mice

The effect of 5-HT and opioid receptor antagonists on morphine-induced Straub tail was studied in mice. Straub tail behavior was induced by subcutaneous administration of different doses (20, 30, and 40 mg/kg) of morphine hydrochloride to mice. The effect of morphine was dose-dependent. Maximum response was obtained with 40 mg/kg of the drug. The response induced by morphine (20 and 40 mg/kg) was decreased by different doses of intraperitoneal injection of naloxone (1 and 2 mg/kg) or methysergide, mianserin, and ritanserin (1 and 2 mg/kg). The effect of morphine (40 mg/kg) was also reduced by intracerebroventricular injection of naloxone (0.4-0.8 microg/animal) or mianserin (2 and 4 microg/animal). Different groups of mice received one daily dose (50 mg/kg sc) of morphine sulfate for 3 days to develop tolerance to morphine. The Straub tail reaction induced by morphine hydrochloride (40 mg/kg) was tested on the fourth day. Naloxone injection (1 and 2 mg/kg ip) on Day 3 (1 h after morphine sulfate injection) or on Day 4 (1 h before test dose of morphine hydrochloride), decreased tolerance induced to morphine. Methysergide, mianserin, or ritanserin (intraperitoneal) on Days 2 and 3 (1 h after morphine sulfate injection) or on Day 4 (1 h before test dose of morphine hydrochloride), also decreased tolerance induced to morphine. Intracerebroventricular injection of either naloxone or mianserin also reduced tolerance to morphine. It is concluded that 5-HT(2) and opioid receptor mechanisms are involved in morphine-induced Straub tail reaction and tolerance induced to morphine also may be mediated through these receptors.     

Effects of olanzapine and other antipsychotic agents on responding maintained by a conflict schedule

The effects of the "atypical" antipsychotic olanzapine and several other antipsychotics were examined using a conflict schedule. Rats were trained to respond for food on a three-component schedule, comprising variable-interval 30s (food, VI30) and fixed-ratio 10s (food + shock, FR10) components separated by time-out (TO). Olanzapine (0.3125-1.25mg/kg), clozapine (1.25-5mg/kg) and chlordiazepoxide (2.5-5mg/kg) decreased or had no effect on VI30 responding, whereas responding in the FR10 component increased. Chlordiazepoxide (5mg/kg) also increased TO responding. The antipsychotic agents haloperidol (0.125 and 0.25mg/kg), trifluoperazine (0.0625-0.25mg/kg), remoxipride (1.25-5mg/kg) and risperidone (0.0625-0.5mg/kg) decreased V130 responding and either had no effect, or decreased TO and FR10 rates. The anticholinergic agent scopolamine (0.03125-0.25mg/kg) decreased VI30 responding. The 5-HT(2) antagonist ritanserin (2.5 and 5mg/kg) and the anticholinergic agent trihexyphenidyl (2.5 and 5mg/kg) had no effect on responding. Flumezanil (10mg/kg) reduced the anticonflict effect of chlordiazepoxide but not olanzapine. These results further emphasize the unusual profile of olanzapine.