The Acetylcholine Esterase Inhibitor Donepezil Increases Dopamine Levels in the Nucleus Accumbens and Blocks the Alcohol Deprivation Effect in Rats

ABSTRACT Alcohol use disorder is associated with substantial morbidity and mortality arising from both medical consequences and accidents. Currently available pharmacotherapies are limited, and novel treatment options are needed. One putative target for pharmacotherapy is the mesolimbic dopamine system and its major target, the nucleus accumbens. Mesolimbic dopamine signaling is regulated by multiple neurotransmitters, among which acetylcholine is a key modulator. This study investigated whether the acetylcholine esterase inhibitor donepezil affects basal and/or alcohol‐induced increases in extracellular dopamine levels in the nucleus accumbens, and whether it influences alcohol consumption in male Wistar rats. Extracellular dopamine levels were measured using in vivo microdialysis, while alcohol intake was assessed using an intermittent two‐bottle choice paradigm followed by alcohol deprivation. Systemic administration of donepezil increased extracellular dopamine levels in the nucleus accumbens, an effect blocked by local administration of the muscarinic antagonist scopolamine but not by the nicotinic antagonist mecamylamine, indicating a primarily muscarinic mechanism. Moreover, following donepezil pretreatment, alcohol administration did not produce any further increase in dopamine. Donepezil did not alter voluntary alcohol consumption under intermittent access conditions, but it fully abolished the alcohol deprivation effect. These findings suggest that donepezil modulates accumbal dopamine transmission via muscarinic receptors and may influence neurobiological mechanisms underlying relapse‐like drinking.