Chronic ethanol self-administration alters dopamine in the caudate nucleus and putamen of rhesus macaques in a sex-dependent manner

Alcohol use disorder (AUD) affects over 28 million people in the U.S and is associated with neurobiological alterations, including in the basal ganglia. Within the basal ganglia, the caudate nucleus (caudate) and putamen are implicated in AUD due to their roles in ethanol reinforcement. The caudate receives inputs from cortico-associative areas, and the putamen receives inputs from somatosensory areas, supporting goal-directed and habitual behaviors, respectively. These distinct behavioral roles are supported by dopamine signaling, including phasic dopamine, which is involved in assessing action-outcome associations, and tonic dopamine, which reflects ongoing dopaminergic tone that biases action initiation. Intrastriatal dopamine release is modulated by cholinergic interneurons via nicotinic acetylcholine receptors. Dysregulation of these mechanisms can contribute to the transition from occasional to habitual ethanol drinking. Here, we used in-vitro fast-scan cyclic voltammetry to measure dopamine signaling in male and female rhesus macaques following six months of ethanol self-administration. In the putamen, ethanol increased tonic dopamine in both sexes, with females exhibiting greater release and faster dopamine uptake rates than males. In the caudate, ethanol self-administration enhanced dopamine uptake rates only in males. Phasic dopamine release was enhanced by ethanol in the caudate of both sexes, but only in the putamen in males. Further, nAChR blockade revealed that phasic dopamine release in ethanol males, but not females, was dependent on cholinergic modulation. These results demonstrate that basal and sex-specific dopamine release and uptake are uniquely altered in rhesus macaque caudate and putamen in conjunction with chronic ethanol drinking.