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Chronic Ethanol Exposure and Withdrawal Impair Synaptic GABA A Receptor‐Mediated Neurotransmission in Deep‐Layer Prefrontal Cortex
Author(s) -
Hughes Benjamin A.,
Bohnsack John Peyton,
O'Buckley Todd K.,
Herman Melissa A.,
Morrow A. Leslie
Publication year - 2019
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.14015
Subject(s) - prefrontal cortex , neurotransmission , neuroscience , inhibitory postsynaptic potential , gabaa receptor , postsynaptic potential , chemistry , receptor , medicine , endocrinology , biology , cognition
Background The prefrontal cortex ( PFC ) acts as an integrative hub for the processing of cortical and subcortical input into meaningful efferent signaling, permitting complex associative behaviors. PFC dysfunction is consistently observed with ethanol (EtOH) dependence and is a core component of the pathology of alcohol use disorders in current models of addiction. While intracortical gamma‐aminobutryric acid (GABA)ergic neurotransmission is understood to be essential for maintaining coordinated network activity within the cortex, relatively little is known regarding functional GABA ergic adaptations in PFC during EtOH dependence. Methods In the present study, male and female (> postnatal day 60) Sprague‐Dawley rats were administered EtOH (5.0 g/kg; intragastric gavage) for 14 to 15 consecutive days. Twenty‐four hours after the final administration, animals were sacrificed and brains extracted for electrophysiological recordings of isolated GABA A receptor‐mediated currents or analysis of GABA A receptor subunit protein expression in deep‐layer PFC neurons. Results Chronic EtOH exposure significantly attenuated activity‐dependent spontaneous GABA A receptor‐mediated inhibitory postsynaptic current ( IPSC ) frequency with no effect on amplitude. Furthermore, analysis of IPSC decay kinetics revealed a significant enhancement of IPSC decay time that was associated with decrements in expression of the α 1 GABA A receptor subunit, indicative of further impaired phasic inhibition. These phenomena occurred irrespective of neuron projection destination and sex. Based on previous observations by our laboratory of an epigenetic mechanism for EtOH‐induced changes in cortical GABA A receptor subunit expression, the histone deacetylase inhibitor Trichostatin A was administered to water‐ and EtOH‐exposed animals, and prevented EtOH‐induced changes in spontaneous IPSC frequency, IPSC decay kinetics, and GABA A receptor subunit expression. Conclusions Taken together, these results demonstrate that chronic EtOH exposure impairs synaptic inhibitory neurotransmission in deep‐layer pyramidal neurons of the medial PFC in both male and female rats. These maladaptations occur in neurons projecting to numerous regions implicated in the sequelae of EtOH dependence, offering a mechanistic link between the manifestation of PFC dysfunction and negative affective states observed with extended consumption.