Effects of Sulfasalazine on BOLD Response to Alcohol Cues

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).