Molecular and behavioral effects mediated by Gs-coupled adenosine A2a, but not serotonin 5-HT4 or 5-HT6 receptors following antipsychotic administration

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-los 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.