Impact of chronic alcohol on neuronal cholinergic signaling

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Project Summary Alcohol use disorder (AUD) is a chronic condition characterized by escalating alcohol intake, preoccupation with alcohol, and continued alcohol use despite adverse consequences. AUD has broad negative health and socioeconomic impacts. AUD is linked to liver disease, birth defects, neurological and psychological complications, weakened immune system, and heart problems. In the US, the economic burden of AUD exceeds $220 billion annually. One facet of AUD is persistent engagement in deleterious behaviors (e.g. alcohol consumption). The inability to alter these behaviors may be due to chronic alcohol-induced deficits in acetylcholine (ACh) signaling. Interestingly, ablation of ACh neurons results in AUD-like behavioral phenotypes. Thus, the experiments proposed in this grant will examine ACh signaling in tissues obtained from rhesus macaques with a history of long-term alcohol self-administration. In the first experiment, the fabrication method for carbon fiber electrodes to measure ACh release will be refined and validated for measurement of ACh release in mouse brain slices (Specific Aim 1a). These validated acetylcholine probes will then be used in two annual necropsies at the Oregon National Primate Research Center where we will measure ACh release in brain regions implicated in AUD (e.g. caudate nucleus, putamen, cingulate & prefrontal cortex) from long-term alcohol self-administering and control macaques (Specific Aim 1b). In the second set of experiments (Specific Aim 2), we will obtain RNA samples from several brain regions from the Monkey Alcohol Tissue Research Resource (MATRR) to compare gene expression of ACh signaling related proteins from the same alcohol self-administering and control macaques used in the necropsies. Altogether, the subjects from these necropsies will include male and female, as well as, alcohol self-administering and control subjects, allowing for multifactorial analysis of any obtained data. Further, our ACh measurements will be correlated with cognitive flexibility measures obtained by the MATRR. Importantly, these results will fill a gap in the AUD literature and make use of an important resource (MATRR) that provides NHP tissues from the most relevant and translatable model of human AUD.