Long-term ethanol self-administration by cynomolgus macaques alters the pharmacology and expression of GABA_A receptors in basolateral amygdala

We have recently demonstrated that chronic ethanol ingestion alters the functional and pharmacological properties of GABA_A receptors measured in acutely isolated rat lateral/basolateral amygdala neurons, a limbic forebrain region involved with fear-learning and innate anxiety. To understand relevance of these results in the context of primates, we have examined the effects of long-term ethanol self-administration on basolateral amygdala GABA_A receptor pharmacology and expression in cynomolgus macaques (Macaca fascicularis). The impact of this 18-month-long exposure on GABAA receptor function was assessed in acutely isolated neurons from basolateral amygdala with whole-cell patch-clamp electrophysiology. Neurons from control animals expressed maximal current densities that were not significantly different from the maximal current densities of neurons from ethanol-treated animals. However, the GABA concentration-response relationships from ethanol-exposed neurons were significantly right-shifted compared with control neurons. These adaptations were associated with significant alterations in some characteristics of macroscopic current desensitization. To understand the mechanism governing these adaptations, we quantified GABAA a subunit mRNAs in basolateral amygdala from the same animals. mRNA levels of the α2 and α3 subunits were significantly decreased, whereas decreases in al expression only approached statistical significance. There were no changes in α4 mRNA levels. These findings indicate that ethanol-induced alterations in GABA_A function may be regulated in part by selective changes in the expression of particular a subunits. We conclude that adaptations of basolateral amygdala GABAA receptors after long-term ethanol self-administration by the cynomolgus macaque are similar, but not identical, to those described in rodents after a brief forced ethanol exposure.