mechanisms of disulfiram-induced cocaine abstinence: antabuse and cocaine relapse

Abstract

The anti-alcoholism drug disulfiram (Antabuse), which is an inhibitor of aldehyde dehydrogenase, induces an aversive reaction to alcohol consumption and thereby helps patients reduce alcohol intake. Recent clinical trials, initiated to investigate whether disulfiram could be used to treat individuals who abuse both alcohol and cocaine, have indicated that disulfiram effectively decreases cocaine consumption. Yet the ability of disulfiram to curb cocaine intake cannot be explained by the disruption of ethanol metabolism. Here, we synthesize clinical and animal data that point to dopamine beta-hydroxylase inhibition as a mechanism underlying the efficacy of disulfiram in the treatment of cocaine dependence.

Meriem Gaval-Cruz, BS, is a graduate student in the Division of Biological and Biomedical Sciences at Emory University. Her research interests focus on the neurobiology of drug addiction, with an emphasis on cocaine pharmacotherapies. Her activities include neuroscience outreach to K-12 students and the laboratory mentoring of undergraduates.

David Weinshenker, PhD, is Associate Professor in the Department of Human Genetics at Emory University. He has pursued model systems to better understand genes involved in human disease. He applies genetic models combined with pharmacological tools to investigate various aspects of neurobiology, with a particular focus on the role of norepinephrine in brain function and disease. Send correspondence to DW. E-mail dweinshenker@genetics.emory.edu; fax 404-727-3949.

Figure 1

Disulfiram inhibition of ethanol metabolism. Ethanol is first converted into acetaldehyde by alcohol dehydrogenase (ADH). Acetaldehyde is then transformed into acetate by aldehyde dehydrogenase (ALDH). Disulfiram inhibits ALDH and thereby results in "the disulfiram-ethanol reaction" that promotes abstinence from alcohol. See text for details.

Figure 2

Dopamine metabolism. Dopamine (DA) is metabolized intracellularly and extracellularly by the same group of enzymes, but in different orders. Inside dopaminergic cells, monoamine oxidase (MAO) converts dopamine into 3,4-dihydrophenylacetaldeyde (DOPAL), a substrate of aldehyde dehydrogenase (ALDH). ALDH then converts DOPAL into 3,4-dihydroxyphenylacetic acid (DOPAC). After DOPAC diffuses out of the cell, catechol-O-methyltransferase (COMT) converts it into homovanillic acid (HVA). Extracellularly, dopamine metabolism begins by transformation into 3-methoxytyramine (3-MT) by COMT. 3-MT is then oxidized into 3-methoxy-4-hydroxyphenylacetaldehyde (MHPA) by MAO, and finally transformed into HVA by ALDH.

Figure 3

Disulfiram inhibition of the norepinephrine (NE) biosynthetic pathway. In the catecholamine synthesis pathway, tyrosine is converted into 3,4-dihydroxy-L-phenylalanine (L-DOPA) by tyrosine hydroxylase (TH), which is then transformed into dopamine by aromatic amino acid decarboxylase (AADC), whereupon dopamine b-hydroxylase (DBH) converts dopamine into norepinephrine. Disulfiram inhibits DBH, reducing the production of norepinephrine and increasing the pool of dopamine.

Figure 4

Effect of chronic DBH inhibition on dopamine transmission. Genetic DBH inhibition, and presumably pharmacological DBH inhibition by disulfiram, leads to decreased norepinephrine synthesis in the locus coeruleus and brainstem and norepinephrine release in the midbrain. Because midbrain dopaminergic neurons require noradrenergic drive for normal burst firing and neurotransmitter release, dopamine release is decreased and a compensatory upregulation of high-affinity state dopamine receptors ensues, resulting in behavioral hypersensitivity to psychostimulants.