Typical antipsychotic agents are potent antagonists of Gi-coupled dopamine D2 receptors, but their mechanisms of action following this initial blockade remain poorly understood. We hypothesized that in striatal neurons, interruption of this inhibitory dopamine D2 input would unmask endogenous striatal Gs-coupled receptors. An increase in cAMP levels generated by these unopposed receptors would then lead to the well-described behavioral and molecular effects of antipsychotic administration such as catalepsy and striatal c-fos and neurotensin gene transcription. We examined three striatal Gs-coupled receptor systems (serotonin 5-HT4, serotonin 5-HT6 and adenosine A2a) to assess their potential involvement in the mechanism of action of the typical antipsychotic haloperidol. Antagonists of each of these three receptor systems together with a 1 mg/kg dose of haloperidol were co-administered to Sprague-Dawley rats, and both the degree of catalepsy produced in the animals and the induction of striatal c-fos and neurotensin messenger RNAs were measured. Both the specific adenosine A2a antagonist 8-(3-chlorostyryl)-caffeine and the general adenosine antagonist theophylline reduced haloperidol-dependent induction of striatal neurotensin and c-fos messenger RNA. Administration of these agents also greatly reduced the degree of catalepsy induced by haloperidol. Antagonists of the 5-HT6 receptor failed to block the induction of striatal messenger RNAs, but the 5-HT6 antagonist clozapine (an important atypical antipsychotic agent in its own right) was a potent inhibitor of catalepsy. 5-HT4 agents were unable to alter haloperidol's effects on striatal messenger RNA levels or catalepsy. We conclude that the striatal Gs-coupled adenosine A2a receptor is an important mediator of the molecular and behavioral sequelae following haloperidol administration.