Neuropeptide Y (NPY) produces anxiolytic effects in rodent models, and naturally occurring low NPY expression in humans has been associated with negative emotional phenotypes. Studies in rodent models have also demonstrated that NPY elicits reward behaviors through its action in the nucleus accumbens (NAc), but the impact of NPY on the human NAc is largely unexplored. We recruited 222 healthy young adults of either sex and genetically selected 53 of these subjects at the extremes of NPY expression (Low-NPY and High-NPY) to participate in functional magnetic resonance imaging. Responses of the NAc and surrounding ventral striatum were quantified during a monetary incentive delay task in which stimuli varied by salience (high versus low) and valence (win versus loss). We found that bilateral NAc responses to high-salience versus low-salience stimuli were greater for Low-NPY subjects relative to High-NPY subjects, regardless of stimulus valence. To our knowledge, these results provide the first evidence in humans linking NPY with salience sensitivity of the NAc, raising the possibility that individual differences in NPY expression moderate the risk for disorders of mesoaccumbal function such as addictions and mood disorders. Additionally, we found that head motion was greater among High-NPY subjects, consistent with previous reports linking NPY with hyperactivity. Future studies in animal models are warranted to elucidate the neural mechanisms through which NPY influences NAc function and related behaviors.

Several studies have suggested that females and males differ in reward behaviors and their underlying neural circuitry. Whether human sex differences extend across neural and behavioral levels for both rewards and punishments remains unclear. We studied a community sample of 221 young women and men who performed a monetary incentive task known to engage the mesoaccumbal pathway and salience network. Both stimulus salience (behavioral relevance) and valence (win vs loss) varied during the task. In response to high- vs low-salience stimuli presented during the monetary incentive task, men showed greater subjective arousal ratings, behavioral accuracy and skin conductance responses (P < 0.006, Hedges’ effect size g = 0.38 to 0.46). In a subsample studied with functional magnetic resonance imaging (n = 44), men exhibited greater responsiveness to stimulus salience in the nucleus accumbens, midbrain, anterior insula and dorsal anterior cingulate cortex (P < 0.02, g = 0.86 to 1.7). Behavioral, autonomic and neural sensitivity to the valence of stimuli did not differ by sex, indicating that responses to rewards vs punishments were similar in women and men. These results reveal novel and robust sex differences in reward- and punishment-related traits, behavior, autonomic activity and neural responses. These convergent results suggest a neurobehavioral basis for sexual dimorphism observed in the reward system, including reward-related disorders.

Ketamine is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor that is both a drug of abuse and an FDA-approved anesthetic used off-label for treatment-resistant depression. Despite its growing clinical use for depression and pain, the relationships between the acute dissociative and affective effects of ketamine that contribute to its abuse liability and therapeutic potential, along with the neural mechanisms underlying these effects, are not well established. To address this need, we have implemented a randomized, double-blinded, placebo-controlled, within-subjects mechanistic trial. Healthy adult subjects undergo infusion with two fixed doses of subanesthetic racemic intravenous (IV) ketamine and placebo and their acute responses are assessed with self-report questionnaires, behavioral measures, hormone levels, and neuroimaging. As planned in our analysis strategy, we present interim results for the first 7 subjects of our study, focusing on dissociative and affective states and resting functional brain coupling signatures of these states. The first key finding was that ketamine induced dose-dependent increases in dissociation and related intoxication. Ketamine also altered affective states, reducing emotional insensitivity but increasing stress assessed by cortisol. Second, ketamine had an effect on altering brain connectivity, particularly for specific connections between regions of the reward and negative affect circuits and involving thalamic sub-regions. Third, regarding brain-response associations, ketamine-induced increases in amygdala-anteroventral thalamus coupling were correlated with greater dissociation and intoxication, whereas decreases in the coupling of the anteromedial thalamus and posterior parietal thalamus were correlated with increased sensory aspects of reward responsiveness. Additional specific correlations were observed between affective measures relevant to reward responsiveness or its absence and drug-altered changes in localized functional connections involving the nucleus accumbens (NAcc), amygdala, and thalamic sub-regions. We also discovered a consistent profile of negative associations between ketamine altered connectivity involving the NAcc and specific thalamic sub-regions and effects of anxiety. Further, drug-altered increases in the coupling of the amygdala and anteroventral thalamus were associated with increases in cortisol, an indicator of biochemical stress. The findings highlight the utility of integrating self-reports, objective measures, and functional neuroimaging to disentangle the brain states underlying specific acute responses induced by ketamine. With the likely continued expansion of FDA indications for ketamine, understanding acute responses and underlying neural mechanisms is important for maximizing the therapeutic potential of ketamine while minimizing the risk of promoting misuse or abuse of this substance. Clinical Trial Registration ID #: NCT03475277