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NEUROPHARMACOLOGY

Long-Term Ethanol Self-Administration by Cynomolgus Macaques Alters the Pharmacology and Expression of GABA_A Receptors in Basolateral Amygdala

Department of Physiology and Pharmacology and the Center for the Neurobehavioral Study of Alcohol, Wake Forest University School of Medicine, Winston-Salem, North Carolina

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 GABA_A 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 GABA_A subunit mRNAs in basolateral amygdala from the same animals. mRNA levels of the 2 and 3 subunits were significantly decreased, whereas decreases in 1 expression only approached statistical significance. There were no changes in 4 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 subunits. We conclude that adaptations of basolateral amygdala GABA_A 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.

Address correspondence to: Dr. Brian A. McCool, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157. E-mail: bmccool{at}wfubmc.edu

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