Abstract
Functional dysregulation of the glutamatergic receptor system during withdrawal from chronic drug exposure is a primary driver of drug craving and relapse. Animal models of psychostimulant use have demonstrated dynamic alterations in both AMPA and NMDA receptor function and expression that contribute to drug seeking behavior. Regulation of these receptor systems can begin as early as a few days following cessation of drug use and are persistently expressed into long term withdrawal (>60d). Short term withdrawal (24hr) from chronic exposure to ethanol also induces functional dysregulation of AMPA and NMDA receptors suggesting that similar mechanisms may be regulating drug craving and relapse behaviors across drugs of abuse. To this end, we investigated NMDA receptor mediated synaptic function during protracted withdrawal (>35d) 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 exposed to repeated cycles of CIE (12hr/day, 4d on/3d off, 3 cycles) demonstrated increased functional contributions of NMDA receptors in male but not female animals in comparison to sex matched control animals exposed to room air (CON). These functional increases occurred at resting (-80mV) and depolarized (+40mV) membrane potentials. Psychostimulant studies showing similar increases at resting potentials (-80mV) have implicated GluN3-containing NMDA receptors as the primary mechanism driving this effect. Pharmacological studies using the GluN2B antagonist ifenprodil, suggest that increased NMDAR contributions in male animals is mediated through GluN2B containing receptors. Interestingly, ifenprodil antagonized the increased responses at both resting and depolarized membrane potentials. These results mirror increased NMDA receptor function found during protracted withdrawal from cocaine self-administration suggesting possible common mechanisms underlying aberrant synaptic function during withdrawal from multiple drugs of abuse. Ongoing studies are focused on elucidating the specific contributions of NMDA receptor subunits (GluN2B/GluN3) to the overall functional increases found and exploring sex differences in NMDA receptor regulation.
Published Version
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