Differential regulation of G protein-coupled receptor-associated proteins in the caudate and the putamen of cynomolgus macaques following chronic ethanol drinking

The dorsal striatum is composed of the caudate nucleus and the putamen in human and non-human primates. These two regions receive different cortical projections and are functionally distinct. The caudate is involved in the control of goal-directed behaviors, while the putamen is implicated in habit learning and formation. Previous reports indicate that ethanol differentially influences neurotransmission in these two regions. Because neurotransmitters primarily signal through G protein-coupled receptors (GPCRs) to modulate neuronal activity, the present study aimed to determine whether ethanol had a region-dependent impact on the expression of proteins that are involved in the trafficking and function of GPCRs, including G protein subunits and their effectors, protein kinases, and elements of the cytoskeleton. Western blotting was performed to examine protein levels in the caudate and the putamen of male cynomolgus macaques that self-administered ethanol for 1 year under free access conditions, along with control animals that self-administered an isocaloric sweetened solution under identical operant conditions. Among the 18 proteins studied, we found that the levels of one protein (PKC beta) were increased, and 13 proteins (G alpha i1/3, G alpha i2, G alpha o, G beta 1 gamma, PKC alpha, PKC epsilon, CaMKII, GSK3 beta, beta-actin, cofilin, alpha-tubulin, and tubulin polymerization promoting protein) were reduced in the caudate of alcohol-drinking macaques. However, ethanol did not alter the expression of any proteins examined in the putamen. These observations underscore the unique vulnerability of the caudate nucleus to changes in protein expression induced by chronic ethanol exposure. Whether these alterations are associated with ethanol-induced dysregulation of GPCR function and neurotransmission warrants future investigation. image The caudate nucleus and the putamen in human and non-human primates are functionally distinct and regulate different aspects of drug-related behavior. We found that long-term ethanol drinking in male cynomolgus macaques results in reduced expression of numerous proteins involved in G protein-coupled receptor trafficking and function in the caudate but not in the putamen. Our data underscore the unique vulnerability of the caudate nucleus to adaptations induced by chronic ethanol exposure.image