The Effects of Chronic Ethanol on GABA Receptors in the Nonhuman Primate Brain

Abstract

The GABAergic system is a well-known molecular target of ethanol. Acute ethanol increases the function of the GABAA receptor, while chronic ethanol decreases function. Rodent studies have reported changes in gene and protein levels, receptor function, and receptor binding density in GABAA receptors and subunits after chronic ethanol, and changes in GABAB gene and protein levels. However, human studies are somewhat scarce, and existing data is often conflicting. In a translational approach, we utilized a nonhuman primate model of chronic ethanol self-administration to investigate total GABAA, alpha1 and alpha 4/6 subunit-containing receptor binding density in a variety of cerebral cortical regions and the cerebellum. Ethanol induces region and layer dependent receptor binding density alterations. In general, drinkers show less dense binding in both cerebral cortical regions and in the cerebellum. There was an upregulation of both the GABAA alpha 1 and GABAB2 subunit gene expression after chronic ethanol. These results indicate that both synaptic and extrasynaptic GABAA receptors are altered by ethanol, but that its effects are dependent on circuitry. Posttranslational modification may occur to account for differences seen between gene expression and receptor binding density results seen here.