Surprisingly, 3-back performance improvement was significant despite the fact that there was no correlation between changes in AHR and RBC DHA/EPA levels following supplementation with n–3 PUFA. The fact that working memory performance was enhanced by n–3 PUFA supplementation regardless of an effect on striatal VMAT2 suggests that its potential pro-cognitive effects, are mediated via extrastriatal dopamine or other non-dopaminergic mechanisms such as effects on inflammation, cellular signaling and trafficking etc. Alternatively other mechanisms that govern the release and storage of dopamine such as afferent regulation of dopamine cell activity or dopamine synthesis may play a role. Future WY 14643 PPAR inhibitor studies are needed to investigate the role of n–3 PUFA on dopamine release mechanisms as well as indices of prefrontal cortical dopamine function. The latter studies are especially critical because prefrontal cortical dopamine is linked to working memory performance. Since the concentration of dopamine in the prefrontal cortex is 10 to 35-fold lower than in the striatum it is likely that a relatively small increase in dopamine following n–3 PUFA supplementation has a greater impact in the cortex and translates to pro-cognitive effects. In addition, the likelihood to detect relatively small changes in dopamine concentration is better in the prefrontal cortex than in the striatum because of the low baseline dopamine levels in this region. Future studies with D1 and D2/3 receptor PET radiotracers to evaluate the effects of n–3 PUFA on prefrontal cortical dopamine and its relationship with working memory are necessary to address these issues. The current investigation was designed as a proof of concept study to clarify whether n–3 PUFA supplementation leads to increased VMAT2 availability in the human striatum. This question arose based on a recent PET imaging study in which we showed that cocaine addicts have lower vesicular monoamine transporter type 2 in the striatum relative to healthy controls. This reduction in VMAT2, which suggests fewer dopamine storage vesicles in the terminals, is one of the mechanisms that lead to the blunted dopamine release in the striatum after a psychostimulant challenge in cocaine addicts compared to controls. In addition, more recent data links this blunted dopamine release in the striatum to relapse and treatment failure in cocaine addicts. Since preclinical studies in rodents signaled that diets deficient in n–3 PUFAs lead to lower striatal VMAT2 density by 25 to 60% and reduce stimulant-induced DA release we were interested in evaluating the potential of n–3 PUFA as means to increase VMAT2 availability, enhance DA storage and release, and prevent relapse in cocaine addicts. The result of this human imaging study suggests that n–3 PUFA supplementation is unlikely to enhance striatal DA transmission in cocaine addicts and promote abstinence. In summary, we found no effect for n–3 PUFA supplementation on striatal VMAT2 availability in healthy humans using DTBZ and PET. Higher RBC DHA levels were associated with better working memory performance in this cohort of young adults, which is consistent with that previously shown in middleaged adults. Also, n–3 PUFA supplementation improved working memory performance, which is consistent with some but not all clinical trials that have evaluated the pro-cognitive effects of n–3 PUFA in humans. Further research is warranted to elucidate the mechanisms by which n–3 PUFA enhances cognitive performance in healthy individuals.