The anxiolytic-like effect of 5-HT1B receptor ligands in rats: a possible mechanism of action

We have examined the effect of lesions of 5-hydroxytryptamine (5-HT) neurons, produced by p-chloroamphetamine (p-CA; 2 × 10 mg kg - 1 ), and the influence of flumazenil (Ro 15-1788, 10 mg kg - 1 ), a benzodiazepine receptorantagonist, on the anxiolytic-like activity of CP 94253 (5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine), a 5-HT 1 B receptor agonist, SB 216641 (N-[3-[3-(dimethylamino)ethoxy]-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-carboxamide), a 5-HT 1 B receptor antagonist, and GR 127935 (N-[4-methoxy-3-(4-methyl-I-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-I, I'-biphenyl-4-carboxamide), a 5-HT 1 B / 1 D receptor antagonist, in the Vogel conflict drinking test in rats. Diazepam was used as a reference compound. CP 94253 (2.5 mg kg - 1 ), SB 216641 (2.5 mg kg - 1 ), GR 127935 (10 mg kg - 1 ) and diazepam (5 mg kg - 1 ) significantly increased the number of shocks accepted during experimental sessions in the conflict drinking test in vehicle- and p-CA-pretreated rats. Flumazenil did not change the anxiolytic-like effect of CP 94253 (2.5 mg kg - 1 ), but wholly blocked the anxiolytic-like effects of SB 216641 (2.5 mg kg - 1 ), GR 127935 (10 mg kg - 1 ) and diazepam (5 mg kg - 1 ). p-CA and flumazenil alone were inactive in the conflict drinking test. The results suggested that the anxiolytic-like effect of the 5-HT 1 B receptor ligands CP 94253, SB 216641 and GR 127935 was possibly linked to the postsynaptic 5-HT 1 B receptors or/and 5-HT 1 B heteroreceptors. The results suggested also that benzodiazepine receptors were indirectly involved in the effects of SB 216641 and GR 127935 (but not of CP 94253), which might have been due to a possible interaction between the 5-HT and the GABA/benzodiazepine systems.