Ethanol interaction with α3β4 nicotinic acetylcholine receptors in neurons of the laterodorsal tegmentum.

Abstract

BACKGROUND\nNicotinic acetylcholine receptors (nAChRs) play a key role in the rewarding effects of ethanol (EtOH), and while several nAChR subtypes have been implicated, attention has recently shifted to a role for the α3β4 nAChR. The laterodorsal tegmental nucleus (LDTg), a brainstem cholinergic nucleus that sends excitatory projections to the ventral tegmental area (VTA), is an Integral part of the brain reward pathway, and here we investigate a potential role for LDTg α3β4 nAChRs in EtOH self-administration and reward.\n\n\nMETHODS\nSprague-Dawley rats were given ad-libitum access to a 20% EtOH solution, as part of a 2-bottle choice paradigm. Approximately one week after removal of EtOH access, we measured LDTg α3β4 nAChR current responses to focal application of acetylcholine (ACh), using whole-cell patch clamp electrophysiology recordings in acute brain slices. In addition, we used whole-cell electrophysiology to assess the acute effects of EtOH on the sensitivity of LDTg α3β4 nAChRs.\n\n\nRESULTS\nFocal application of ACh onto LDTg neurons resulted in large α3β4 nAChR mediated inward currents, the magnitude of which showed a positive correlation with levels of EtOH self-administration. In addition, using brain slices taken from EtOH naïve rats, bath application of EtOH resulted in a moderate potentiation of LDTg α3β4 nAChR sensitivity.\n\n\nCONCLUSIONS\nIncreased α3β4 nAChR function in high EtOH drinkers, along with positive modulation by EtOH, may predispose towards increased EtOH consumption, thus identifying the α3β4 nAChR as a potentially important therapeutic target in the treatment of EtOH use disorder.