Non-specific inhibition of dopamine receptor agonist-induced behaviour by the tachykinin NK1 receptor antagonist CP-99,994 in guinea-pigs

Abstract

Evidence that tachykinin NK1 receptors selectively modulate activity in the mesolimbic dopamine pathway suggests an antipsychotic potential for tachykinin NK1 receptor antagonists. We investigated the ability of the antagonist CP-99,994 (and the less active enantiomer CP-100,263) to block dopamine receptor agonist-induced behaviour in guinea-pigs. The active dose range for inhibition of [Sar9,Met(O2)11]substance P-induced behaviour by CP-99,994 was 1-3 mg/kg s.c. The same doses of CP-100,263 were without effect. In contrast, both CP-99,994 (20 or 30 mg/kg) and CP-100,263 (10-30 mg/kg) antagonised behavioural stimulation induced by the dopamine receptor agonists amphetamine (1 mg/kg i.p.) or (+)-PHNO ((+)-4-propyl-9-hydroxy-naphthoxazine hydrochloride; 0.1 mg/kg s.c.). Lower doses of CP-99,994 or CP-100,263 were not active. These findings do not support the proposal that tachykinin NK1 receptors in the terminal projection area of the mesolimbic system can modify dopamine-mediated behaviour.