ROLE OF ACCUMBENS AND CORTICAL DOPAMINE-RECEPTORS IN THE REGULATION OF CORTICAL ACETYLCHOLINE-RELEASE

Cortical acetylcholine, under resting and stimulated conditions, was m easured in frontoparietal and prefrontal cortex using in vivo microdia lysis in freely-moving rats. Cortical acetylcholine efflux was stimula ted by systemic administration of the benzodiazepine receptor partial inverse agonist FG 7142. Administration of FG 7142 (8.0 mg/kg; i.p.) s ignificantly elevated acetylcholine efflux in both cortical regions (1 50-250% relative to baseline) for 30 min after drug administration. Th e ability of endogenous dopamine to regulate cortical acetylcholine ef flux under resting or stimulated conditions and the relative contribut ions of D-1- and D-2-like dopamine receptor activation was also assess ed. In a first series of experiments, systemic administration of the a ntipsychotic drug haloperidol (0.15, 0.9 mg/kg, i.p.) blocked FG 7142- stimulated acetylcholine efflux in frontoparietal, cortex while the D- 1-like antagonist, SCH 23390 (0.1, 0.3 mg/kg), was less effective in a ttenuating stimulated acetylcholine efflux. In a second series of expe riments, the effects of infusions of these antagonists and of the D-2- like antagonist sulpiride (10, 100 mu M) into the nucleus accumbens we re assessed. Infusions of haloperidol and sulpiride significantly bloc ked FG 7142-stimulated acetylcholine efflux while SCH 23390 did not. B y contrast, a third series of experiments demonstrated that perfusion of these antagonists (100 mu M) locally into the cortex (through the p robe) did nut affect FG 7142-stimulated acetylcholine emus. Moreover, none of these dopamine receptor antagonists, whether administered syst emically or perfused into the nucleus accumbens or cortex, affected ba sal cortical acetylcholine efflux. These results reveal similarities i n stimulated cortical acetylcholine release across frontal cortical re gions and suggest a prominent rule for D-2-mediated accumbens dopamine transmission in the regulation of cortical acetylcholine release. The findings provide evidence in support of a neural substrate that links dysregulation of mesolimbic dopaminergic transmission to changes in c ortical cholinergic transmission. Dysregulation within this circuit is hypothesized to contribute to the etiology of disorders such as schiz ophrenia, dementia and drug abuse. (C) 1998 IBRO. Published by Elsevie r Science Ltd.