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NEUROPHARMACOLOGY

Chronic Ethanol Ingestion Facilitates N-Methyl-D-aspartate Receptor Function and Expression in Rat Lateral/Basolateral Amygdala Neurons

Wake Forest University School of Medicine, Department of Physiology and Pharmacology; Winston-Salem, North Carolina (D.W.F., B.A.M.); and Texas A&M University Health Science Center, Department of Medical Pharmacology and Toxicology, College Station, Texas (K.-Y.J.)

Withdrawal anxiety after chronic alcohol is likely to contribute to drug seeking and relapse in alcoholics. The brain regions regulating fear/anxiety behaviors, especially neurotransmitter systems with acute ethanol sensitivity, are potential targets for chronic ethanol-induced adaptations. We have therefore examined N-methyl-D-aspartate (NMDA) receptors after chronic ethanol ingestion in rat lateral/basolateral amygdala. Whole cell patch-clamp measurements indicate that chronic ethanol ingestion significantly increased NMDA receptor current density. This enhanced NMDA receptor function was also associated with an increase in ifenprodil inhibition and a decrease in apparent calcium-dependent current inactivation. These findings suggest that NR2B-containing receptors may be specifically enhanced and suggest that processes dependent upon calcium influx through amygdala NMDA receptors may potentially be enhanced by chronic ethanol ingestion. We measured subunit mRNA expression to investigate possible molecular mechanisms that control functional receptor adaptations to chronic ethanol. Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) demonstrated that NR1 subunit mRNA expression, but not NR2 or NR3 expression, was enhanced in samples from chronic ethanol-exposed animals. Single-cell RT-PCR was then used to confirm that NR2 mRNA expression was unaltered by chronic ethanol. Most GAD^–, presumed projection neurons expressed both NR2A and NR2B mRNAs, and this profile did not change during chronic ethanol exposure. Our results suggest that both transcriptional and nontranscriptional adaptations to chronic ethanol ultimately contribute to alterations in NMDA receptor function. Because amygdala NMDA receptors play a significant role in many learned fear behaviors, chronic ethanol-induced adaptations in these receptors may influence the expression of withdrawal anxiety.

Address correspondence to: Dr. Brian A. McCool, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, 115 S. Chestnut, Winston-Salem, NC 27157. E-mail: bmccool{at}wfubmc.edu

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