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.
Phase:
Phase 2
Details
Lead Sponsor:
Bankole Johnson
Collaborators:
National Institute on Alcohol Abuse and Alcoholism (NIAAA) National Institutes of Health (NIH)