title: 5-HT(1B/D) receptor agonist, SKF99101H, induces locomotor hyperactivity in the guinea pig.
abstract: Previous studies in guinea pigs have shown that while a serotonin 5-HT(1B/D) receptor agonist, GR46611, does not induce locomotor activation when given alone, it markedly enhances the locomotor response to selective 5-HT(1A) receptor agonists, 8-OH-DPAT and buspirone. In these studies, we found that another 5-HT(1B/D) agonist, 3-(2-dimethylaminoethyl)-4-chloro-5-propoxyindole hemifumarate (SKF99101H), significantly elevated locomotor activity in guinea pigs when given alone. We assessed the relative contribution of 5-HT1(1A) and 5-HT(1B/D) receptors in the mediation of this effect. Activity was measured by photobeam interrupts in opaque Perspex cylinders linked to a computer. SKF99101H (20 mg/kg s. c.) significantly increased the locomotor activity in guinea pigs. The locomotor stimulant effect of SKF99101H (20 mg/kg s.c) was reversed by the selective 5-HT(1B/D) receptor antagonist N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl -1,2,4-oxadiazol-3-yl)[1,1biphenyl]4-carboxamide (GR127935; 0.06-0. 25 mg/kg s.c.). The 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY100635; 0.05-0.25 mg/kg s.c.), slightly but significantly attenuated the hyperactivity induced by SKF99101H. These findings suggest that 5-HT(1B/D) receptor agonists may require concomitant activation of 5-HT(1A) receptors to induce locomotor activity in guinea pigs. The 5-HT(2A) receptor antagonist 6[2-[4-[bis(4-fluorophenyl)methylene]-1-piperidinyl]-ethyl]-7-methyl- 5H-thiazol[3,2-a]pyrimidin-5-one (ritanserin) had no effect on SKF99101H-induced hyperactivity, suggesting that these receptors are not involved in the mediation of SKF99101H-induced hyperactivity. SKF99101H-induced hyperactivity was significantly 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 (0.25-1.0 mg/kg), possibly suggesting the selective involvement of D(1) dopaminergic receptors in the mediation of the stimulant actions of the 5-HT(1B/D) agonist.
authors.affiliation: Lilly Research Centre, Erl Wood Manor, Sunninghill Road, Windlesham, GU20 6PH, Surrey, UK. oneill_michael_f@lilly.com
authors.forename: M F
authors.initials: MF
authors.lastname: O'Neill
authors.forename: D R
authors.initials: DR
authors.lastname: Dobson
authors.forename: G J
authors.initials: GJ
authors.lastname: Sanger
mesh_terms: D000818:Animals; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D007211:Indoles / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects*; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
chemical_list: D018492:Dopamine Antagonists; D007211:Indoles; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; C108517:SKF 99101H