Comparative behavioural profiles of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) in the murine elevated plus-maze.
It has been suggested that in vivo formation of the metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) may be a major drawback in the use of buspirone as an anti-anxiety agent. To test this hypothesis, the effects of buspirone, alone or with proadifen (an inhibitor of liver microsomal enzymes) pretreatment, were contrasted with those of 1-PP in the murine elevated plus-maze test of anxiety. At 3.0 mg/kg (but not lower doses), buspirone per se had modest anxiolytic-like effects (increased percentage of open arm entries; reduced stretched-attend postures and flatback approach) that were associated with increased grooming and immobility. However, in proadifen-pretreated mice, buspirone produced behavioural depression only, with marked effects evident both at 1.0 and 3.0 mg/kg. As proadifen blocks the biotransformation of buspirone to 1-PP, these data suggest that any anxiolytic activity of buspirone in the murine plus-maze may be attributable to its principal active metabolite. Consistent with this hypothesis, 1-PP (0.5-13.5 mg/kg) produced dose-dependent anti-anxiety effects on both conventional and ethological measures that were not confounded by motoric impairment. Results are discussed in relation to biochemical and electrophysiological studies suggesting that 1-PP has a direct action at 5-HT1A receptors.
Cao
B J
BJ
Department of Psychology, University of Leeds, U.K.
Rodgers
R J
RJ
D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism / Q000494:pharmacology*; D001711:Biotransformation; D002065:Buspirone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D004336:Drug Antagonism; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D011335:Proadifen / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology*
D014151:Anti-Anxiety Agents; D017366:Serotonin Receptor Agonists; D011335:Proadifen; C037921:1-(2-pyrimidinyl)piperazine; D002065:Buspirone