Ethanol tolerance and synaptic plasticity

doi:10.1016/S0165-6147(98)01268-1

Trends in Pharmacological Sciences

Volume 19, Issue 12, 1 December 1998, Pages 491-495

https://doi.org/10.1016/S0165-6147(98)01268-1 Get rights and content

Abstract

Current concepts of the mechanisms underlying many of the pharmacological effects of ethanol on the CNS involve disruption of ion channel function via the interaction of ethanol with specific hydrophobic sites on channel subunit proteins. Of particular clinical importance is the development of tolerance and dependence to ethanol, and it is likely that adaptive changes in synaptic function in response to ethanol's actions on ion channels play a role in this process. In this article, Judson Chandler, Adron Harris and Fulton Crews discuss potential mechanisms of ethanol-induced changes in synaptic function that might provide a cellular basis for ethanol tolerance and dependence. It is proposed that multiple mechanisms are involved that include both transcriptional and post-translational modifications in NMDA and GABA_A receptors.

Section snippets

NMDA and GABA_A receptors

The major excitatory and inhibitory neurotransmitters in the brain are glutamate and GABA, respectively, and ionotropic glutamate [NMDA, (rs)-α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate] and GABA_A receptors are among the most widely distributed and abundant receptor-operated ion channels in the CNS. Both NMDA and GABA_A receptors are composed of multiple subunit proteins, which are thought to assemble as hetero-pentameric structures that exhibit distinct properties

Mechanisms of ethanol tolerance

Tolerance can include changes at the behavioural level (behavioural tolerance) and at the cellular level (physiological tolerance). Behavioural tolerance is thought to be a learned response to overcome alcohol-induced behaviours and can be observed in chronic alcoholics and non-alcoholic social drinkers. Physiological tolerance is viewed as a compensatory change at the cellular level in response to the depressant effects of ethanol, and can be temporally divided into rapid (minutes to hours)

Concluding remarks

Inhibition of NMDA and potentiation of GABA_A receptors by acute ethanol results in reduced synaptic activity that is likely to contribute to the intoxicating effects of ethanol. It is probable that alteration in synaptic function by ethanol exposure contributes to the development of physiological tolerance that involves changes in excitatory glutamate-mediated and inhibitory GABA-mediated neurotransmission. Acute tolerance might involve post-translational modifications such as receptor

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¹: Assistant Professor

²: Professor

³: Director, Bowles Center for Alcohol Studies, and Professor

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Trends in Pharmacological Sciences

ViewpointEthanol tolerance and synaptic plasticity

Abstract

Section snippets

NMDA and GABAA receptors

Mechanisms of ethanol tolerance

Concluding remarks

Trends Pharmacol. Sci.

Int. Rev. Neurobiol.

Brain Res.

J. Biol. Chem.

Brain Res.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Brain Res.

Brain Res.

Neuropharmacology

Int. Rev. Neurobiology

Mol. Brain Res.

J. Biol. Chem.

Brain Res.

J. Biol. Chem.

Neuron

Int. Rev. Neurobiol.

Neuron

Cell

Neuron

Neuron

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Neuron

J. Biol. Chem.

Trends Pharmacol. Sci.

Physiol. Rev.

J. Pharmacol. Exp. Ther.

Mol. Pharmacol.

Alcohol. Clin. Exp. Res.

Proc. Natl. Acad. Sci. U. S. A.

J. Pharmacol. Exp. Ther.

Science

Viewpoint
Ethanol tolerance and synaptic plasticity

NMDA and GABA_A receptors