Chronic Ethanol Exposure and Withdrawal Impair Synaptic GABAA Receptor‐Mediated Neurotransmission in Deep‐Layer Prefrontal Cortex

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 GABAergic 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 GABAA receptor-mediated currents or analysis of GABAA receptor subunit protein expression in deep-layer PFC neurons. RESULTS Chronic EtOH exposure significantly attenuated activity-dependent spontaneous GABAA 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 α1 GABAA 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 GABAA 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 GABAA 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.

• Publication year

  2019

• Venue

  Alcoholism: Clinical and Experimental Research

• Publication date

  2019-04-18

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1111/acer.14015PMID 30860602PMCID PMC6502689
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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