Intra-Accumbal Infusions of an α2-Adrenoceptor Agonist and an α2-Adrenoceptor Antagonist Respectively Inhibit and Enhance Acetylcholine but Not Dopamine Efflux in the Nucleus Accumbens of Freely Moving Rats.

Though the nucleus accumbens (NAc) is a key terminal region of the mesolimbic dopaminergic system, it is also innervated by noradrenergic inputs from the ventral medulla and contains intrinsic cholinergic neurons. However, the roles of α-adrenoceptors in regulating basal accumbal cholinergic activity remain unclear. This study employed in vivo microdialysis in unanesthetized rats to investigate the role of α1- and α2-adrenoceptors in modulating extracellular acetylcholine (ACh) levels in the NAc. Accumbal administration of the α2-agonist UK 14304 (30.0 and 300.0 pmol) and the α2-antagonist RX 821002 (0.6, 600.0, and 6000.0 pmol) dose-dependently decreased and increased accumbal ACh efflux, respectively. Neither compound (UK 14304: 300.0 pmol; RX 821002: 6000.0 pmol) affected basal accumbal dopamine levels. Co-administration of RX 821002 (0.6 pmol) blocked the UK 14304 (300.0 pmol)-induced reduction in ACh efflux, whereas UK 14304 (30.0 pmol) inhibited the RX 821002 (6000.0 pmol)-induced increase. Intraperitoneal administration of RX 821002 (1.0 mg/kg), but not UK 14304 (2.5 mg/kg), increased accumbal ACh efflux, which was inhibited by intra-accumbal infusion of UK 14304 (30.0 pmol). Neither the α1-agonist methoxamine (0.24 pmol) nor the α1-antagonist prazosin (6.0 pmol) altered accumbal ACh levels. Doses of drugs infused indicate the total amount (mol) during the 60-min infusion. These findings indicate that RX 821002 enhances ACh efflux in the NAc by blocking accumbal α2-adrenoceptor-mediated inhibition of ACh release. Given that reduced accumbal ACh levels have been implicated in cognitive impairment, systemic administration of α2-adrenoceptor antagonists should be investigated for their potential to improve such deficits in experimental models.