Dataset Information

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

ABSTRACT: 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 ?1 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.

SUBMITTER: Hughes BA

PROVIDER: S-EPMC6502689 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Chronic Ethanol Exposure and Withdrawal Impair Synaptic GABA<sub>A</sub> Receptor-Mediated Neurotransmission in Deep-Layer Prefrontal Cortex.

Hughes Benjamin A BA Bohnsack John Peyton JP O'Buckley Todd K TK Herman Melissa A MA Morrow A Leslie AL

Alcoholism, clinical and experimental research 20190418 5

<h4>Background</h4>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 coor ...[more]

PMID: 30860602

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Project description:BackgroundThe medial prefrontal cortex (PFC) is crucial for regulating craving and alcohol seeking in alcohol use disorder (AUD) patients and alcohol seeking in animal models. Maladaptive changes in volitional ethanol (EtOH) intake have been associated with PFC function, yet synaptic adaptations within PFC have not been consistently detected in voluntary drinking rodent models. At least 80% of the neurons in PFC are glutamatergic pyramidal cells. Pyramidal cells provide the predominant cortical output to several brain regions relevant to AUD, including structures within the telencephalon (IT: e.g., basal ganglia, amygdala, other neocortical regions) and outside the telencephalon (ET: e.g., lateral hypothalamus, midbrain monoaminergic structures, thalamus).MethodsIn addition to their anatomical distinctions, studies from several laboratories have revealed that prefrontal cortical IT and ET pyramidal cells may be differentiated by specific electrophysiological parameters. These distinguishable parameters make it possible to readily classify pyramidal cells into separable subtypes. Here, we employed and validated the hyperpolarization sag ratio as a diagnostic proxy for separating ET (type A) and IT (type B) neurons. We recorded from deep-layer prelimbic PFC pyramidal cells of mice 1 day after 4 to 5 weeks of intermittent access (IA) EtOH exposure.ResultsMembrane properties were not altered by IA EtOH, but excitatory postsynaptic strength onto IT type B neurons was selectively enhanced in slices from IA EtOH mice. The increased excitatory drive was accompanied by enhanced mGlu2/3 receptor plasticity on IT type B neurons, providing a potential translational approach to mitigate cognitive and motivational changes to PFC function related to binge drinking.ConclusionsTogether, these studies provide insight into the specific PFC neurocircuits altered by voluntary drinking. In addition, the findings provide an additional rationale for developing compounds that potentiate mGlu2 and/or mGlu3 receptor function as potential treatments for AUD.

Dataset Information

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

Publications

Chronic Ethanol Exposure and Withdrawal Impair Synaptic GABA<sub>A</sub> Receptor-Mediated Neurotransmission in Deep-Layer Prefrontal Cortex.

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