Elucidating the biological basis for the reinforcing actions of alcohol in the mesolimbic dopamine system: the role of active metabolites of alcohol

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Abstract

The development of successful pharmacotherapeutics for the treatment of alcoholism is predicated upon understanding the biological action of alcohol. A limitation of the alcohol research field has been examining the effects of alcohol only and ignoring the multiple biological active metabolites of alcohol. The concept that alcohol is a “pro-drug” is not new. Alcohol is readily metabolized to acetaldehyde within the brain. Acetaldehyde is a highly reactive compound that forms a number of condensation products, including salsolinol and iso-salsolinol (acetaldehyde and dopamine). Recent experiments have established that numerous metabolites of alcohol have direct CNS action, and could, in part or whole, mediate the reinforcing actions of alcohol within the mesolimbic dopamine system. The mesolimbic dopamine system originates in the ventral tegmental area (VTA) and projects to forebrain regions that include the nucleus accumbens (Acb) and the medial prefrontal cortex (mPFC) and is thought to be the neurocircuitry governing the rewarding properties of drugs of abuse. Within this neurocircuitry there is convincing evidence that; (1) biologically active metabolites of alcohol can directly or indirectly increase the activity of VTA dopamine neurons, (2) alcohol and alcohol metabolites are reinforcing within the mesolimbic dopamine system, (3) inhibiting the alcohol metabolic pathway inhibits the biological consequences of alcohol exposure, (4) alcohol consumption can be reduced by inhibiting/attenuating the alcohol metabolic pathway in the mesolimbic dopamine system, (5) alcohol metabolites can alter neurochemical levels within the mesolimbic dopamine system, and (6) alcohol interacts with alcohol metabolites to enhance the actions of both compounds. The data indicate that there is a positive relationship between alcohol and alcohol metabolites in regulating the biological consequences of consuming alcohol and the potential of alcohol use escalating to alcoholism.

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Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.

G Di Chiara, A. Imperato (1988)

The effect of various drugs on the extracellular concentration of dopamine in two terminal dopaminergic areas, the nucleus accumbens septi (a limbic area) and the dorsal caudate nucleus (a subcortical motor area), was studied in freely moving rats by using brain dialysis. Drugs abused by humans (e.g., opiates, ethanol, nicotine, amphetamine, and cocaine) increased extracellular dopamine concentrations in both areas, but especially in the accumbens, and elicited hypermotility at low doses. On the other hand, drugs with aversive properties (e.g., agonists of kappa opioid receptors, U-50,488, tifluadom, and bremazocine) reduced dopamine release in the accumbens and in the caudate and elicited hypomotility. Haloperidol, a neuroleptic drug, increased extracellular dopamine concentrations, but this effect was not preferential for the accumbens and was associated with hypomotility and sedation. Drugs not abused by humans [e.g., imipramine (an antidepressant), atropine (an antimuscarinic drug), and diphenhydramine (an antihistamine)] failed to modify synaptic dopamine concentrations. These results provide biochemical evidence for the hypothesis that stimulation of dopamine transmission in the limbic system might be a fundamental property of drugs that are abused.

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Overview: How Is Alcohol Metabolized by the Body?

Samir Zakhari (2006)

Alcohol is eliminated from the body by various metabolic mechanisms. The primary enzymes involved are aldehyde dehydrogenase (ALDH), alcohol dehydrogenase (ADH), cytochrome P450 (CYP2E1), and catalase. Variations in the genes for these enzymes have been found to influence alcohol consumption, alcohol-related tissue damage, and alcohol dependence. The consequences of alcohol metabolism include oxygen deficits (i.e., hypoxia) in the liver; interaction between alcohol metabolism byproducts and other cell components, resulting in the formation of harmful compounds (i.e., adducts); formation of highly reactive oxygen-containing molecules (i.e., reactive oxygen species [ROS]) that can damage other cell components; changes in the ratio of NADH to NAD+ (i.e., the cell’s redox state); tissue damage; fetal damage; impairment of other metabolic processes; cancer; and medication interactions. Several issues related to alcohol metabolism require further research.

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Alcoholism: a systems approach from molecular physiology to addictive behavior.

Rainer Spanagel (2009)

Alcohol consumption is an integral part of daily life in many societies. The benefits associated with the production, sale, and use of alcoholic beverages come at an enormous cost to these societies. The World Health Organization ranks alcohol as one of the primary causes of the global burden of disease in industrialized countries. Alcohol-related diseases, especially alcoholism, are the result of cumulative responses to alcohol exposure, the genetic make-up of an individual, and the environmental perturbations over time. This complex gene x environment interaction, which has to be seen in a life-span perspective, leads to a large heterogeneity among alcohol-dependent patients, in terms of both the symptom dimensions and the severity of this disorder. Therefore, a reductionistic approach is not very practical if a better understanding of the pathological processes leading to an addictive behavior is to be achieved. Instead, a systems-oriented perspective in which the interactions and dynamics of all endogenous and environmental factors involved are centrally integrated, will lead to further progress in alcohol research. This review adheres to a systems biology perspective such that the interaction of alcohol with primary and secondary targets within the brain is described in relation to the behavioral consequences. As a result of the interaction of alcohol with these targets, alterations in gene expression and synaptic plasticity take place that lead to long-lasting alteration in neuronal network activity. As a subsequent consequence, alcohol-seeking responses ensue that can finally lead via complex environmental interactions to an addictive behavior.

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Author and article information

Journal

Journal ID (nlm-ta): Front Behav Neurosci

Journal ID (iso-abbrev): Front Behav Neurosci

Journal ID (publisher-id): Front. Behav. Neurosci.

Title: Frontiers in Behavioral Neuroscience

Publisher: Frontiers Media S.A.

ISSN (Electronic): 1662-5153

Publication date (Electronic preprint): 01 June 2013

Publication date (Electronic): 23 August 2013

Publication date Collection: 2013

Volume: 7

Electronic Location Identifier: 104

Affiliations

Department of Psychiatry, Institute of Psychiatric Research, Indiana University, School of Medicine Indianapolis, IN, USA

Author notes

Edited by: Elio Acquas, University of Cagliari, Italy

Reviewed by: Miriam Melis, University of Cagliari, Italy; Roberto Ciccocioppo, University of Camerino, Italy; Yedy Israel, University of Chile, Chile

*Correspondence: Gerald A. Deehan Jr, Department of Psychiatry, Institute of Psychiatric Research, Indiana University, School of Medicine, 791 Union Drive, Indianapolis, IN 46202-4887, USA e-mail: gdeehan@ 123456iupui.edu

This article was submitted to the journal Frontiers in Behavioral Neuroscience.

Article

DOI: 10.3389/fnbeh.2013.00104

PMC ID: 3750600

PubMed ID: 23986666

SO-VID: 436fe2e5-5299-422b-8f52-43d4ed71104a

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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

History

Date received : 06 May 2013

Date accepted : 27 July 2013

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Figures: 2, Tables: 0, Equations: 0, References: 177, Pages: 13, Words: 12178

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Most cited references 162

Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.

Overview: How Is Alcohol Metabolized by the Body?

Alcoholism: a systems approach from molecular physiology to addictive behavior.

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