The D2 dopamine receptor (DRD2) was another top finding from the TWAS analysis (Figure 3 top), with significant predicted decreased expression in the nucleus accumbens. The mesolimbic dopamine reward circuit, of which nucleus accumbens is a critical part, has long been implicated in depression.22 A recent optogenetic study examining dopaminergic ventral tegmental area (VTA) projections into nucleus accumbens found that dopamine receptors are required for the action of these neurons in depression-related escape behavior.23 Depression-like behavior in animals might be related to depression in humans through links to the reward system and symptoms of anhedonia. A recent randomized proof-of-mechanism trial24 investigated κ-opioid antagonists (KOR) as treatment for anhedonia symptoms. KORs localize within the nucleus accumbens on the terminals of inputs from the mesolimbic dopamine reward circuit. Among the actions of KORs antagonists might be normalization of VTA KOR function and D2 neurons activation, leading to disinhibition of the excitatory circuit they project upon.25 Indeed, the KOR JNJ-67953964 was found to increase VTA activation relative to placebo during reward anticipation, highlighting a potential therapeutic mechanism by which KOR is thought to
