GR46611 potentiates 5-HT 1A receptor-mediated locomotor activity in the guinea pig

Abstract

5-HT 1B/D receptor agonists such as GR46611 (3-[3-(2-Dimethylaminoethyl)- H-indol-5-yl]- N-(4-methoxybenzyl)acrylamide) are known to lower body temperature in guinea pigs. Although stimulation of their functional analogs in rats, the 5-HT 1B receptor induces hyperlocomotion, this effect has yet to be demonstrated with 5-HT 1B/D receptor agonists in the guinea pig. Previous studies have shown that 5-HT 1A agonists increase locomotor activity in guinea pigs. The current study set out to examine the effects of 5-HT 1B/D receptor stimulation on locomotor activity in the guinea pig and to examine the interaction between 5-HT 1A and 5-HT 1B/D receptor stimulation on locomotor activity in that species. The full agonist at 5-HT 1A receptors, 8-OH-DPAT ( R(+)-8-Hydroxy-dipropylaminotetralin HBr) dose-dependently increased locomotor activity in guinea pigs (0.3–1.25 mg kg −1 s.c.), as to a lesser extent, did the partial agonist, buspirone (8-[4-[4-(2-Pyramidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione HCl) (5.0–20.0 mg kg −1 s.c.). The 5-HT 1B/D receptor agonist GR46611 had no effect on locomotor activity in guinea pigs at doses up to 40 mg kg −1 s.c. 8-OH-DPAT-induced behavioural activation was reversed by the selective 5-HT 1A receptor antagonist WAY100635 ( N-[-2-[4-(-methoxyphenyl)-1-piperazinyl]ethyl]- N-(pyrinidyl) cyclo hexanocarboxamide trihydro-chloride), with a minimum effective dose of 0.006 mg kg −1, but not by the 5-HT 1B/D receptor antagonist GR127935 (2′-methyl-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)phenyl]-amide) (0.25–1.0 mg kg −1). GR46611, at doses that were without effect given alone (0.5–2.5 mg kg −1), significantly enhanced the locomotor response to subthreshold doses of 8-OH-DPAT (0.5 mg kg −1) and buspirone (10 mg kg −1). The effect of GR46611 on 8-OH-DPAT-induced hyperactivity was reversed by pretreatment with GR127935 and with WAY 100635 indicating that activation of both receptors was required for the expression of locomotor hyperactivity. These findings suggest that activation of 5-HT 1B/D receptors alone may not stimulate locomotor activity but it does potentiate the locomotion induced by 5-HT 1A receptor stimulation in guinea pigs.