fMRI Imaged Neuroactivation & Craving in Alcoholics is Modulated by Ondansetron

Methods to assess acute medjca60n effects on brain function and behavior have not been developed for an alcoholic population. This highly novel multidisciplinary study, consistent with ACCP's Research Agenda and Domains, will determine if phannacologic functional Magnetic Resonance Imaging (fMRI) can be a tool to measure cue-induced neuroactivation and alcohol craving in alcoholics, and to detennine whether the intravenous (IV) probe medication ondansetron (OND) can acutely modulate these biomarkers. Previous research has demonstrated that daily oral OND administration is an effective therapeutic intervention for suppressing alcohol craving and drinking in adolescent and early stage aJcoholics. Craving symptoms, which create a risk for relapse, can be triggered by various social and environmental cues; the influence of such cues can be significant during various stages of recovery. Yet, no medications, which when taken acutely, are intended to reduce acute craving symptoms or urges. Acute interventional relapse-prevention medication approaches, to be used when patients are or anticipate being in a high-risk situation, have been heretofore unavailable. Thus, this study proposes a new tool, phannacological-fMRI, to measure acute medication effects in alcoholics. The tool can be used to develop new phannacologic treatment options for alcoholics. The long-tenn objective is to validate that fMRI can be a tool to assess acute effects of medications and delivery systems on brain function and behavior in alcoholics. The specific aims are to: 1. Detennine whether (fMRl) and Blood Oxygen Level Dependent (BOLD) signal can serve as a tool to measure cue-induced neuroactivation and real-time urges to drink in alcoholics; 2. Detennine whether IV OND acutely reduces cue-induced neuroactivation and patient craving; 3. Detennine whether a phannacokinetic-dynamic model can relate drug exposure to outcomes. The hypotheses of this project are that: 1) cue-induced neuroactivation and craving can be measured during fMRI; and, 2) that IV OND, as compared to IV placebo, will reduce alcohol- specific cued neuroactivation in relevant regions of the brain such as the nucleus acumbens, insula and cingulate gyrus. The project hypotheses will be tested by the following methods: 1. Conduct an fMRI study of IV OND versus placebo in non-abstinent, non-treatment seeking alcoholics. 2. Demonstrate neuroactivation, as demonstrated by enhanced BO LD signal in the nucleus acumbens, and associated secondary brain structures, utilizing a taste prime and visual alcohol-specific cue provocation as compared to control image cues. 3. Demonstrate parallel and concurrent with fMRI real-time increase in patient craving symptoms. 4. Demonstrate IV OND rapidly reduces neuroactivation and craving and correlate to OND pharmacokinetics.