Editors' ChoiceNeuroscience

Stress and alcohol abuse

Sci. Signal.  08 Nov 2016:
Vol. 9, Issue 453, pp. ec265
DOI: 10.1126/scisignal.aal3018

Stress is associated with a risk for alcohol abuse. Among its effects on various neurotransmitter signaling, ethanol stimulates dopamine (DA) release in the mesolimbic system [comprising neuronal circuitry between the ventral tegmental area (VTA) and the nucleus accumbens (NAc)], which is the “reward center” of the brain. Ethanol is an agonist for γ-aminobutyric acid type A (GABAA) receptors, which serve as ligand-gated ion channels to allow chloride ion movement across the cell membrane. Under normal conditions, the opening of GABAA receptors permits the hyperpolarizing influx of chloride ions to reduce postsynaptic nerve activity. In the VTA, GABA-releasing neurons synapse with the DA-releasing neurons. Ethanol reduces the activity of the GABA-releasing neurons, which alleviates GABAergic inhibition (a process called disinhibition) of postsynaptic DA neurons. Using mouse models, Ostroumov et al. found that stress acting through the hormone glucocorticoid triggers ionic changes in the VTA that result in ethanol-mediated stimulation of GABAA receptors enhancing the activity of the GABA neurons, which reduces the activity of DA neurons. Mice subjected to acute restraint stress ingested more ethanol yet exhibited less extracellular DA in the VTA compared with control nonstressed mice, but these effects in stressed mice were prevented by systemic or intra-VTA injection of the glucocorticoid receptor antagonist RU486. Electrophysiology analysis of VTA DA neurons both in vivo (in mice that were stressed then 15 hours later anesthetized and administered ethanol intravenously) and ex vivo (in midbrain slices isolated 15 hours after stress and bathed in ethanol) revealed that prior stress prevented ethanol-induced increase in VTA DA neuron firing. The K+,Cl transporter KCC2 establishes the Cl gradient in neurons by transporting Cl out of the cell. Dephosphorylation of KCC2 at Ser940 is associated with reduced Cl extrusion capacity, which increases intracellular Cl accumulation, collapses the Cl gradient, and stimulates bicarbonate extrusion, shifting equilibrium potential for the GABAA receptor such that stimulation of the receptor increases the activity rather than inhibits the activity of the neurons. Experiments with slices exposed to various pharmacological reagents revealed that glucocorticoid-induced dephosphorylation of KCC2 at Ser940 on the presynaptic (GABA-releasing) neuron enhanced the firing rate of GABA neurons in response to ethanol. In vivo and ex vivo, application of the carbonic anhydrase acetazolamide or a pharmacological KCC2 activator to the VTA blocked the stress-induced increase in VTA GABA neuron activity and the stress-induced reduction in NAc DA concentration. Intra-VTA infusion of acetazolamide or the KCC2 activator CLP290 also decreased daily alcohol consumption in stressed mice; neither compound changed alcohol intake in control unstressed mice. The findings reveal a mechanism linking stress and alcoholism and might lead to strategies to prevent its development in at-risk patients.

A. Ostroumov, A. M. Thomas, B. A. Kimmey, J. S. Karsch, W. M. Doyon, J. A. Dani, Stress increases ethanol self-administration via a shift toward excitatory GABA signaling in the ventral tegmental area. Neuron 92, 493–504 (2016). [PubMed]

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