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
TL;DR
Findings indicate that RX 821002 enhances ACh efflux in the NAc by blocking accumbal α2‐adrenoceptor‐mediated inhibition of ACh release, which is implicated in cognitive impairment and systemic administration of α2‐adrenoceptor antagonists should be investigated for their potential to improve such deficits in experimental models.
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 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.