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Increased NMDA receptor function during protracted withdrawal from chronic intermittent ethanol exposure
Daniel T. Christian, PhD
Physiology and Pharmacology Department, Des Moines University, Des Moines, IA
Functional dysregulation of the glutamate system during withdrawal from chronic drug exposure is a primary driver of drug craving and relapse. Animal models of psychostimulant use have demonstrated dynamic NMDA receptor function and expression that contribute to drug seeking behavior. These changes begin as early as 5 days into abstinence and are persistently expressed into long term withdrawal (>60d). Evidence of NMDA receptor dependent changes during short term withdrawal (24h) suggest that similar mechanisms may drive drug craving and relapse behaviors following chronic exposure to ethanol. To this end, we investigated NMDA receptor mediated synaptic function during protracted withdrawal from chronic intermittent ethanol (CIE) exposure using whole cell patch clamp electrophysiology. We focused on the basolateral amygdala (BLA), as glutamatergic signaling in this region is robustly modulated by short term (24h) withdrawal from CIE (10d, 12hr/day) and regulates anxiety like behavior expressed during withdrawal. Adolescent rats were exposed to repeated cycles of CIE (12hr/day, 4d on/3d off, 3 cycles). Male rats demonstrated increased functional contributions of NMDA receptors containing GluN2B and/or GluN3 in comparison to animals exposed to room air (CON) after >35days of withdrawal. Female rats demonstrated no change in NMDA receptor mediated function at similar time points. Results in males mirror cocaine self-administration data suggesting a possible common mechanism underlying aberrant synaptic function during withdrawal. Further characterization of females is ongoing to determine mechanisms of resilience or time dependency in this population.