Elsevier

Addictive Behaviors

Volume 29, Issue 7, September 2004, Pages 1465-1479
Addictive Behaviors

Topiramate-induced neuromodulation of cortico–mesolimbic dopamine function: A new vista for the treatment of comorbid alcohol and nicotine dependence?

https://doi.org/10.1016/j.addbeh.2004.06.014Get rights and content

Abstract

Alcohol and nicotine dependence are commonly occurring disorders that together represent the most important preventable causes of morbidity and mortality in the United States. While there have been differences of opinion as to which disorder to treat first when they occur, there is growing evidence that a management strategy addressing both conditions contemporaneously would be optimal.

Advances in the neurosciences have demonstrated not only that the reinforcing effects of both alcohol and nicotine are mediated by similar mechanisms resulting in enhanced activity of the cortico–mesolimbic dopamine system, but that their neurochemical interactions can lead to an aggregation of these effects. Despite this striking neurobiological overlap between alcohol and nicotine consumption, few studies have sought to take advantage of this commonality by devising a pharmacological approach that serves to treat both disorders. The results of our proof-of-concept study showed that topiramate is a promising medication for the treatment of both alcohol and nicotine dependence, presumably by its ability to modulate cortico–mesolimbic dopamine function profoundly; however, other mechanisms might also contribute to this effect. Further studies are ongoing to establish and extend topiramate's efficacy in the treatment of each and both disorders.

Introduction

Alcohol and nicotine dependence are commonly occurring disorders and, together, represent the most important preventable cause of morbidity and mortality in the United States (Miller & Gold, 1998, Mokdad et al., 2004). At a superficial level, it might appear that the cooccurrence of these disorders is simply a reflection of their high independent prevalence rates in the general population or that these behaviors may be linked by occurring commonly within similar social settings or circumstances. Advances in the neurosciences have, however, shown that there are important neurochemical pharmacodynamic interactions between alcohol and nicotine that might summate to increase codependency on both (Littleton & Little, 2002). Furthermore, there is evidence that pharmacokinetic factors associated with the absorption, distribution, and metabolism of both compounds might lead individuals to administer these compounds in such a way that the effects of one of these drugs serve to modulate the effects of the other (Blomqvist et al., 2002, Seaton & Vesell, 1993). Emerging genetic evidence also shows that an earlier onset of smoking is associated with greater likelihood of problem drinking, and fetal exposure to alcohol may increase susceptibility to smoking (Lê, 2002, Prendergast et al., 2002). Nevertheless, despite this striking evidence for substantial neurochemical and biological overlap between alcohol and nicotine dependence, few clinical trials have addressed the possibility of using a common pharmacological approach to treat both disorders simultaneously.

This overview aims to show the epidemiological relationship between alcohol and nicotine dependence, to demonstrate how the neuropharmacological effects of both drugs are associated with their habit-forming properties, and to provide a framework for a common pharmacological approach using the anticonvulsant, topiramate; it concludes by summarizing the results of a recent clinical trial that examined the effects of topiramate on both alcohol and smoking behavior among dependent individuals.

Section snippets

Epidemiology

Previous studies assessing the relationship between alcohol dependence and smoking have suggested a strong connection between the two. In sample sizes ranging from 103 to 1010, surveys of both inpatient and outpatient treatment participants for alcohol dependence showed an 86–97% smoking rate among males and an 82–92% rate among females (Ayers et al., 1976, Bien & Burge, 1990, Burling et al., 1989, Burling & Ziff, 1988, Dreher & Fraser, 1967, Kozlowski et al., 1986, Walton, 1972). Recently,

Neurochemical interactions between alcohol and nicotine

Important neurochemical interactions exist between alcohol and nicotine that can serve to increase the reinforcing effects and, therefore, abuse liability of the combination.

The reinforcing effects of both nicotine and alcohol are mediated through cortico–mesolimbic dopamine pathways (Hemby, 2003, Hemby et al., 1997, Wise & Bozarth, 1987). While the primary action by which alcohol exerts its reinforcing effects is through the disinhibition of the inhibitory effects of γ-amino-butyric acid-A

General mechanisms of action

Topiramate is a novel anticonvulsant that is approved by the Food and Drug Administration for the treatment of childhood epilepsy. However, it is currently under intense investigation as a treatment for a wide range of neuropsychiatric disorders, including alcohol, nicotine, and drug dependence. Topiramate is a sulfamate-substituted analog of fructose-1,6-diphosphate. Its chemical nomenclature is 2,3:4,5-Di-o-isopropylidene-β-d-fructopyranose sulfamate (Fig. 1). From Fig. 1, it can also be seen

Summary

Alcohol and nicotine dependence are commonly occurring disorders that together represent the most important preventable causes of morbidity and mortality in the United States (Miller & Gold, 1998, Mokdad et al., 2004). While there have been differences of opinion as to which disorder to treat first when they occur, there is growing evidence that a management strategy addressing both conditions contemporaneously would be optimal.

Advances in the neurosciences have demonstrated not only that the

Acknowledgments

I thank the National Institute on Alcohol Abuse and Alcoholism for its support through grants AA 10522-08, 12964-01, and 14628-01; the National Institute on Drug Abuse for its support through grant DA 12191-05; the staff at the South Texas Addiction Research and Technology (START) Center, and Robert H. Cormier, Jr. for his assistance with manuscript preparation.

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