Intra‐Accumbal Infusions of an α ₂ ‐Adrenoceptor Agonist and an α ₂ ‐Adrenoceptor Antagonist Respectively Inhibit and Enhance Acetylcholine but Not

ABSTRACT

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 α ₁ ‐ and α ₂ ‐adrenoceptors in modulating extracellular acetylcholine (ACh) levels in the NAc. Accumbal administration of the α ₂ ‐agonist UK 14304 (30.0 and 300.0 pmol) and the α ₂ ‐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 α ₁ ‐agonist methoxamine (0.24 pmol) nor the α ₁ ‐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 α ₂ ‐adrenoceptor‐mediated inhibition of ACh release. Given that reduced accumbal ACh levels have been implicated in cognitive impairment, systemic administration of α ₂ ‐adrenoceptor antagonists should be investigated for their potential to improve such deficits in experimental models.