The selective dopamine D2 receptor antagonist raclopride discriminates between dopamine-mediated motor functions

Abstract

The actions on central dopamine (DA) mechanisms of raclopride, a new substituted benzamide, were studied by means of behavioural and biochemical methods in the rat. Raclopride blocked the in vitro binding of the dopamine D₂ antagonist ³H-spiperone (IC₅₀=32 nM), but not of the unselective D₁ antagonist ³H-flupenthixol (IC₅₀>100,000 nM) in rat striatum, and failed to inhibit striatal DA-sensitive adenylate cyclase in vitro (IC₅₀>100,000 nM). Raclopride caused a dose-dependent increase in the DA metabolites HVA and DOPAC in the striatum and olfactory tubercle. Behavioural studies showed that raclopride discriminates between the motor behaviours induced by the DA agonist apomorphine. Thus, unlike haloperidol, raclopride blocked apomorphine-induced hyperactivity at considerably lower doses than those inhibiting oral stereotypies. Moreover, raclopride showed a high separation between the doses for blockade of apomorphine-induced hyperactivity and those inducing catalepsy in rats. Raclopride caused a dose-dependent blockade of the specific binding of ³H-spiperone and ³H-N-n-propylnorapomorphine (³H-NPA) in vivo at doses similar to those blocking the behavioural effects of apomorphine. The maximal blockade of ³H-spiperone binding in vivo was lower for raclopride than for haloperidol. Raclopride caused a greater inhibition of ³H-NPA than of ³H-spiperone in vivo binding in the striatum. It is suggested that the ability of raclopride to discriminate between different DA-mediated functions may be attributed to a preferential blockade of a subclass of functionally coupled dopamine D₂ receptors in striatal as well as in extrastriatal brain regions in the rat.