Lesopitron

Abstract: The aim of the present study was to examine the effects of N-(2-(4-2-methoxphenyl)-1-piperazinyl)ethyl)-N-(2-pyridnyl) cyclohexane carboxamide (WAY 100635) on 5-HT1A receptor-mediated responses in the dorsal raphe nucleus (DRN) and the CA1 hippocampal region. In DRN slices superfused with WAY 100635 (10 nM), the majority of putative 5-HT neurons increased their firing rate (13 +/- 2% of baseline rate). In addition, WAY 100635 completely prevented the decrease in firing rate produced by 5-HT (3-15 microM), 8-OH-DPAT (10 nM), 5-carboxamidotryptamine (20 nM) and lesopitron (100 nM). The antagonism exerted by WAY 100635 (IC50 = 0.95 +/- 0.12 nM against 15 microM 5-HT) was fully surmounted by increasing the concentration of 5-HT to 300 microM. In hippocampal slices, WAY 100635 (0.5-10 nM) did not alter the resting membrane potential or the membrane input resistance of intracellularly recorded CA1 pyramidal cells. However, WAY 100635 completely prevented (IC50 = 0.9-1.7 nM) the hyperpolarization and the decrease in membrane input resistance produced by 5-HT (15-30 microM) and by 5-carboxamidotryptamine (50-300 nM). In contrast, WAY 100635 affected neither the block of action potential frequency adaptation and slow afterhyperpolarization produced by 5-HT (15 microM) nor the hyperpolarization and decrease in membrane input resistance evoked by bath application of GABA(B) receptor agonist baclofen (10 microM). The cumulative concentration-hyperpolarization curve for 5-carboxamidotryptamine (3 nM-10 microM) was shifted to the right by WAY 100635 (apparent Kb = 0.23 +/- 0.07 nM), and the latter drug also reduced the maximal response to the agonist. These data show the WAY 100635 is a potent antagonist at 5-HT1A receptors, both in the DRN and in the CA1 region of the hippocampus. The antagonism is apparently competitive in the DRN and partly noncompetitive in the hippocampus. Kinetic characteristics of the antagonist-receptor interactions might account for these regional differences.

Abstract: 1 The ability of 5-HT2 and 5-HT4 receptor antagonists to modify the disinhibitory profile of diazepam and other agents was investigated in male BKW mice in the light/dark test box 2 The 5-HT2A/2B/2C receptor antagonists ritanserin, MDL11939 and RP62203 and also methysergide, which failed to modify mouse behaviour when administered alone, caused dose-related enhancements (4 to 8 fold) in the potency of diazepam to disinhibit behavioural responding to the aversive situation of the test box 3 Ritanserin was shown to enhance the disinhibitory potency of other benzodiazepines, chlordiazepoxide (4 fold), temazepam (10 fold) and lorazepam (10 fold), the 5-HT1A receptor ligands, 8-OH-DPAT (25 fold), buspirone (100 fold) and lesopitron (500 fold), the 5-HT3 receptor antagonists, ondansetron (100 fold) R(+)-zacopride (100 fold) and S(−)-zacopride (greater than a 1000 fold), the substituted benzamides, sulpiride (10 fold) and tiapride (5 to 10 fold) and the cholecystokinin (CCK)A receptor antagonist, devazepide (100 fold) It also reduced the onset of action of disinhibition following treatment with the 5-HT synthesis inhibitor parachlorophenylalanine Ritanserin failed to enhance the disinhibitory effects of the CCKB receptor antagonist CI-988, the angiotensin AT1 receptor antagonist losarten or the angiotensin converting enzyme inhibitor ceranapril 4 The 5-HT4 receptor antagonists SDZ205-557, GR113808 and SB204070 caused dose-related reductions in the disinhibitory effect of diazepam, returning values to those shown in vehicle treated controls The antagonists failed to modify mouse behaviour when administered alone 5 GR113808 was also shown to cause a dose-related antagonism of the disinhibitory effects of chlordiazepoxide, lorazepam, 8-OH-DPAT, buspirone, lesopitron, ondansetron, R(+)-zacopride, sulpiride, tiapride, devazepide, CI-988, losarten, ceranapril and parachlorophenylalanine 6 It was concluded that in BKW mice (a) the failure of 5-HT2 and 5-HT4 receptor antagonists when administered alone to modify behaviour in the light/dark test indicates an absence of an endogenous 5-HT tone at the 5-HT2 and 5-HT4 receptors and (b) the enhancement by the 5-HT2 receptor antagonists and attenuation by the 5-HT4 receptor antagonists of drug-induced disinhibition indicates a plurality of 5-HT receptor involvement in the mediation of drug-induced disinhibitory profiles in the mouse British Journal of Pharmacology (1997) 122, 1105–1118; doi:101038/sjbjp0701513