Molecular and behavioral effects mediated by Gs-coupled adenosine A2a, butnot serotonin 5-HT4 or 5-HT6 receptors following antipsychotic administration
Rp. Ward et Dm. Dorsa, Molecular and behavioral effects mediated by Gs-coupled adenosine A2a, butnot serotonin 5-HT4 or 5-HT6 receptors following antipsychotic administration, NEUROSCIENC, 89(3), 1999, pp. 927-938
Typical antipsychotic agents are potent antagonists of Gi-coupled dopamine
D-2 receptors, but their mechanisms of action following this initial blocka
de remain poorly understood. We hypothesized that in striatal neurons, inte
rruption of this inhibitory dopamine D-2 input would unmask endogenous stri
atal Gs-coupled receptors. An increase in cAMP levels generated by these un
opposed receptors would then lead to the well-described behavioral and mole
cular effects of antipsychotic administration such as catalepsy and striata
l c-fos and neurotensin gene transcription. We examined three striatal Gs-c
oupled receptor systems (serotonin 5-HT4, serotonin 5-HT6 and adenosine A2a
) to assess their potential involvement in the mechanism of action of the t
ypical antipsychotic haloperidol. Antagonists of each of these three recept
or 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 a
nimals and the induction of striatal c-fos and neurotensin messenger RNAs w
ere measured. Both the specific adenosine A2a antagonist 8-(3-chlorostyryl)
-caffeine and the general adenosine antagonist theophylline reduced haloper
idol-dependent induction of striatal neurotensin and c-fos messenger RNA. A
dministration of these agents also greatly reduced the degree of catalepsy
induced by haloperidol. Antagonists of the 5-HT6 receptor failed to block t
he 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 eff
ects on striatal messenger RNA levels or catalepsy.
We conclude that the striatal Gs-coupled adenosine A2a receptor is an impor
tant mediator of the molecular and behavioral sequelae following haloperido
l administration. (C) 1999 IBRO. Published by Elsevier Science Ltd.