Role of accumbens and cortical dopamine receptors in the regulation of cortical acetylcholine release.
Cortical acetylcholine, under resting and stimulated conditions, was measured in frontoparietal and prefrontal cortex using in vivo microdialysis in freely-moving rats. Cortical acetylcholine efflux was stimulated by systemic administration of the benzodiazepine receptor partial inverse agonist FG 7142. Administration of FG 7142 (8.0 mg/kg; i.p.) significantly elevated acetylcholine efflux in both cortical regions (150-250% relative to baseline) for 30 min after drug administration. The ability of endogenous dopamine to regulate cortical acetylcholine efflux under resting or stimulated conditions and the relative contributions of D1- and D2-like dopamine receptor activation was also assessed. In a first series of experiments, systemic administration of the antipsychotic drug haloperidol (0.15, 0.9 mg/kg, i.p.) blocked FG 7142-stimulated acetylcholine efflux in frontoparietal, cortex while the D1-like antagonist, SCH 23390 (0.1, 0.3 mg/kg), was less effective in attenuating stimulated acetylcholine efflux. In a second series of experiments, the effects of infusions of these antagonists and of the D2-like antagonist sulpiride (10, 100 microM) into the nucleus accumbens were assessed. Infusions of haloperidol and sulpiride significantly blocked FG 7142-stimulated acetylcholine efflux while SCH 23390 did not. By contrast, a third series of experiments demonstrated that perfusion of these antagonists (100 microM) locally into the cortex (through the probe) did not affect FG 7142-stimulated acetylcholine efflux. Moreover, none of these dopamine receptor antagonists, whether administered systemically or perfused into the nucleus accumbens or cortex, affected basal cortical acetylcholine efflux. These results reveal similarities in stimulated cortical acetylcholine release across frontal cortical regions and suggest a prominent role for D2-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 cortical cholinergic transmission. Dysregulation within this circuit is hypothesized to contribute to the etiology of disorders such as schizophrenia, dementia and drug abuse.
Moore
H
H
Department of Psychology and Neuroscience Program, The Ohio State University, Columbus 43210, USA.
Fadel
J
J
Sarter
M
M
Bruno
J P
JP
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002243:Carbolines / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000502:physiology*; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D011954:Receptors, Dopamine / Q000502:physiology*
D001552:Benzazepines; D002243:Carbolines; D018492:Dopamine Antagonists; D018756:GABA Antagonists; D011954:Receptors, Dopamine; C035874:FG 7142; D006220:Haloperidol; D000109:Acetylcholine