In the last decade, there has been an explosion of new knowledge of the neuroscientific basis of alcohol-seeking behavior. Briefly, medications that modulate mesolimbic dopamine pathways by facilitating gamma amino butyric function and inhibiting the action of excitatory amino acids should reliably diminish alcohol's rewarding effects. Topiramate (a sulfamate-substituted fructo-pyranose derivative) has these characteristics. In support of this concept, we have shown in a phase-II-type medications clinical trial that topiramate is significantly superior to placebo at improving drinking outcomes and decreasing craving among (N = 150) alcohol-dependent individuals. Using the carefully controlled environment of the human laboratory, we are submitting a revised application containing a set of systematic studies to assess directly the mechanistic neuropharmacological processes that are associated with topiramate's anti-drinking effects. This will provide a more comprehensive understanding of the neurobiology of alcohol-seeking behavior and aid in the development of even more effective compounds for the treatment of alcohol dependence. Thus, the specific aims of the project are to: 1) determine the dose-relationship of acute effects of topiramate to reduce alcohol effects related to its abuse and addiction potential. We hypothesize that topiramate will reduce alcohol-induced craving, reward, and euphoria; 2) determine whether chronic treatment with an acutely effective dose of topiramate produces substantial reductions in alcohol-related cue-induced craving, thereby decreasing the potential for treatment relapse. We hypothesize that chronic topiramate administration will desensitize (reduce) alcohol craving produced by alcohol-related sensory cues; and 3) determine whether topiramate interactions with and without alcohol are associated with neurocognitive impairment. Clinical studies including ours have suggested that topiramate use may be associated with neurocognitive effects such as loss of concentration and memory impairment. In our own study, these effects were mild and not associated with reduced treatment compliance. Since alcohol's ability to produce neurocognitive impairment may be mediated through similar ionic mechanisms to that of topiramate, the proposed human laboratory setting affords us the unique opportunity to more clearly delineate topiramate's neurocognitive effects in both the presence and absence of alcohol. This study supports NIAAA's goal to develop effective medications for treating alcoholism and to understand the basic underpinnings of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA014628-04
Application #
7278719
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Fertig, Joanne
Project Start
2004-09-28
Project End
2009-12-31
Budget Start
2007-09-01
Budget End
2009-12-31
Support Year
4
Fiscal Year
2007
Total Cost
$354,065
Indirect Cost
Name
University of Virginia
Department
Psychiatry
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Johnson, Bankole A; Messing, Robert O; Charness, Michael E et al. (2011) Should the reorganization of addiction-related research across all the National Institutes of Health be structural?--The devil is truly in the details. Alcohol Clin Exp Res 35:572-80
Johnson, Bankole A; Ait-Daoud, Nassima; Seneviratne, Chamindi et al. (2011) Pharmacogenetic approach at the serotonin transporter gene as a method of reducing the severity of alcohol drinking. Am J Psychiatry 168:265-75
Johnson, Bankole A; Ait-Daoud, Nassima (2010) Topiramate in the new generation of drugs: efficacy in the treatment of alcoholic patients. Curr Pharm Des 16:2103-12
Johnson, Bankole A (2010) Medication treatment of different types of alcoholism. Am J Psychiatry 167:630-9
Ait-Daoud, Nassima; Roache, John D; Dawes, Michael A et al. (2009) Can serotonin transporter genotype predict craving in alcoholism? Alcohol Clin Exp Res 33:1329-35
Liu, Lei; Ma, Jennie Z; Johnson, Bankole A (2008) A multi-level two-part random effects model, with application to an alcohol-dependence study. Stat Med 27:3528-39
Johnson, Bankole A; Javors, Martin A; Roache, John D et al. (2008) Can serotonin transporter genotype predict serotonergic function, chronicity, and severity of drinking? Prog Neuropsychopharmacol Biol Psychiatry 32:209-16
Johnson, Bankole A (2008) Update on neuropharmacological treatments for alcoholism: scientific basis and clinical findings. Biochem Pharmacol 75:34-56
Johnson, Bankole A (2006) A synopsis of the pharmacological rationale, properties and therapeutic effects of depot preparations of naltrexone for treating alcohol dependence. Expert Opin Pharmacother 7:1065-73
Ait-Daoud, Nassima; Malcolm Jr, Robert J; Johnson, Bankole A (2006) An overview of medications for the treatment of alcohol withdrawal and alcohol dependence with an emphasis on the use of older and newer anticonvulsants. Addict Behav 31:1628-49

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