The overarching objective of this pilot study is to apply both neuroimaging and pharmacogenetic tools to the study of alcohol dependence. This proposed research will provide a mechanistic test of the function of the genetic variation. The specific aims and hypotheses are to test whether Sulfasalazine, as compared to placebo, diminishes blood-oxygen-level dependent (BOLD) response to alcohol cues in the striatum and prefrontal cortex (PFC). To test the hypothesis, we will compare Sulfasalazine treatment with placebo treatment on BOLD difference maps for the contrast alcohol minus control. We will also explore whether specific genetic variations influence this effect.

Several recent studies support the premise that genetic differences may predict treatment outcomes. In an early study, an A to G single nucleotide polymorphism (SNP; rs1799971) of the mu opiate receptor gene (OPRM1) predicted 12 week abstinence after treatment of alcohol dependence with naltrexone (Oslin et al 2003). The relationship was such that individuals with at least one copy of the G allele demonstrated lower relapse rates and longer time to return to heavy drinking when treated with naltrexone (Oslin et al 2003). These observations were recently replicated and extended in the multisite COMBINE study, such that individuals with the G allele demonstrated superior outcomes after treatment with naltrexone, in combination with medication management (Anton et al 2008). Laboratory studies have suggested that clinical effects may be related to a greater reduction in the acute rewarding effects of alcohol among individuals with the G allele (Ray \& Hutchison 2007) and suggest that the mechanism may be related to a blunting of dopamine release in the VTA (Ramchandani et al 2009). In addition, recent studies with other medications (e.g., topiramate, olanzapine) have found that genetic variables predict treatment outcomes (e.g., Hutchison et al 2006; Hutchison 2008; Seneviratne et al 2009). It is important to note that these gene by treatment interactions are not limited to pharmacological treatments, as recent studies have also suggested that genetic variation may predict responses to psychosocial interventions as well (Feldstein Ewing et al 2009; Hutchison et al 2006).

We decided to evaluate the clinical effects of Sulfasalazine because our work to date suggests that genetic variations with downstream function implications for glutamate function, specifically cysteine/glutamate exchange and glutamate transport, are strongly associated with BOLD response in the striatum and prefrontal cortex after exposure to alcohol cues. Sulfasalazine is a medication with a well characterized safety profile that has been used in the treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease and several types of arthritis, particularly rheumatoid arthritis for many years. Most recently, it has been suggested that Sulfasalazine may have beneficial effects in the brain, specifically by blocking N-methyl D-aspartate receptor-mediated excitotoxicity resulting in reduced neuronal death (Bo Rum Ryu et al, 2003). This pilot study will help to determine whether NMDA receptors play a role in cue-elicited activation of key areas of the brain implicated in the development and maintenance of substance use disorders. Furthermore, if Sulfasalazine reduces cue-elicited activation of these brain regions, as hypothesized; this study will lay the groundwork for a larger trial on the efficacy of Sulfasalazine as a treatment for substance use disorders.

To that end, a double-blind, placebo-controlled 2 (Medication: Sulfasalazine 1500 mg vs. placebo control) x 2 (Cue: Alcohol Cue vs. Control cue) within-subjects, crossover design will be used to test the hypothesis that Sulfasalazine reduces the BOLD response in the striatum and prefrontal cortex after exposure to alcohol cues. Twenty alcohol-dependent participants will complete two rounds of the study medication followed by an fMRI scan, during which they will complete an alcohol cue-exposure task. The order of the medication condition will be counterbalanced such that subjects will be randomly assigned to receive either Sulfasalazine (1500 mg) in the first session and placebo in the second session one week later (or vice versa).