5-HT1B/D receptor agonist, SKF99101H, induces locomotor hyperactivity in the guinea pig

Previous studies in guinea pigs have shown that while a serotonin 5-HT1B/D receptor agonist, GR46611, does not induce locomotor activation when given alone, it markedly enhances the locomotor response to selective 5-HT1A rece ptor agonists, 8-OH-DPAT and buspirone. In these studies, we found that ano ther 5-HT1B/D agonist, 3-(2-dimethylaminoethyl)-4-chloro-5-propoxyindole he mifumarate (SKF99101H), significantly elevated locomotor activity in guinea pigs when given alone. We assessed the relative contribution of 5-HT1(1A) and 5-HT1B/D receptors in the mediation of this effect. Activity was measured by photobeam interrupts in opaque Perspex cylinders l inked to a computer. SKF99101H (20 mg/kg s.c.) significantly increased the locomotor activity in guinea pigs. The locomotor stimulant effect of SKF991 01H (20 mg/kg s.c) was reversed by the selective 5-HT1B/D receptor antagoni st N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4/-(5-methyl-1, 2,4-oxadiazol-3-yl)[1,1 biphenyl]4-carboxamide (GR127935; 0.06-0.25 mg/kg s .c.). The 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperaziny l]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY100635 ; 0.05-0.25 mg/kg s.c.), slightly but significantly attenuated the hyperact ivity induced by SKF99101H. These findings suggest that 5-HT1B/D receptor a gonists may require concomitant activation of 5-HT1A, receptors to induce l ocomotor activity in guinea pigs. The 5-HT2A receptor antagonist 6[2-[4-[bi s(4-fluorophenyl)methylene]-1-piperidinyl]-ethyl]-7-methyl-5H-thiazol[3,2-a ]pyrimidin-5-one (ritanserin) had no effect on SKF99101H-induced hyperactiv ity, suggesting that these receptors are not involved in the mediation of S KF99101H-induced hyperactivity. SKF99101H-induced hyperactivity was signifi cantly attenuated by the D-1 dopamine receptor antagonist SCH 23390 (0.005- 025 mg/kg), but not by the D-2 dopamine receptor antagonist raclopride (0.2 5-1.0 mg/kg), possibly suggesting the selective involvement of D-1 dopamine rgic receptors in the mediation of the stimulant actions of the 5-HT1B/D ag onist. (C) 2000 Elsevier Science B.V. All rights reserved.