The endogenous opioid system, which alleviates physical pain, is also known to regulate social distress and reward in animal models. To test this hypothesis in humans (n = 18), we used a μ-opioid receptor (MOR) radiotracer to measure changes in MOR availability in vivo with positron emission tomography (PET) during social rejection (not being liked by others) and acceptance (being liked by others). Social rejection significantly activated the MOR system (i.e., reduced receptor availability relative to baseline) in the ventral striatum, amygdala, midline thalamus, and periaqueductal gray (PAG). This pattern of activation is consistent with the hypothesis that the endogenous opioids play a role in reducing the experience of social pain. Greater trait resiliency was positively correlated with MOR activation during rejection in the amygdala, PAG, and subgenual anterior cingulate cortex (sgACC), suggesting that MOR activation in these areas is protective or adaptive. In addition, MOR activation in the pregenual ACC was correlated with reduced negative affect during rejection. In contrast, social acceptance resulted in MOR activation in the amygdala and anterior insula, and MOR deactivation in the midline thalamus and sgACC. In the left ventral striatum, MOR activation during acceptance predicted a greater desire for social interaction, suggesting a role for the MOR system in social reward. The ventral striatum, amygdala, midline thalamus, PAG, anterior insula, and ACC are rich in MORs and comprise a pathway by which social cues may influence mood and motivation. MOR regulation of this pathway may preserve and promote emotional well-being in the social environment.

The μ-opioid receptor (MOR) system, well known for dampening physical pain, is also hypothesized to dampen “social pain.” We used positron emission tomography scanning with the selective MOR radioligand [11C]carfentanil to test the hypothesis that MOR system activation in response to social rejection and acceptance is altered in medication-free patients diagnosed with current major depressive disorder (MDD, n = 17) compared to healthy controls (HCs, n = 18). During rejection, MDD patients showed reduced MOR activation (e.g., reduced endogenous opioid release) in brain regions regulating stress, mood, and motivation, and slower emotional recovery compared to HCs. During acceptance, only HCs showed increased social motivation, which was positively correlated with MOR activation in the nucleus accumbens, a reward structure. Abnormal MOR function in MDD may hinder emotional recovery from negative social interactions and decrease pleasure derived from positive interactions. Both effects may reinforce depression, trigger relapse, and contribute to poor treatment outcomes.

Mesoaccumbal and nigrostriatal projections are sensitive to stress, and heightened stress sensitivity is thought to confer risk for neuropsychiatric disorders. Serotonin 2C (5-HT2C) receptors mediate the inhibitory effects of serotonin on dopaminergic circuitry in experimental animals, and preclinical findings have implicated 5-HT2C receptors in motivated behaviors and psychotropic drug mechanisms. In humans, a common missense single-nucleotide change (rs6318, Cys23Ser) in the 5-HT2C receptor gene (HTR2C) has been associated with altered activity in vitro and with clinical mood disorders. We hypothesized that dopaminergic circuitry would be more sensitive to stress in humans carrying the Ser23 variant. To test this hypothesis, we studied 54 healthy humans using positron emission tomography and the displaceable D2/D3 receptor radiotracer [11C]raclopride. Binding potential (BPND) was quantified before and after a standardized stress challenge consisting of 20 minutes of moderate deep muscular pain, and reduction in BPND served as an index of dopamine release. The Cys23Ser variant was genotyped on a custom array, and ancestry informative markers were used to control for population stratification. We found greater dopamine release in the nucleus accumbens, caudate nucleus, and putamen among Ser23 carriers, after controlling for sex, age, and ancestry. Genotype accounted for 12% of the variance in dopamine release in the nucleus accumbens. There was no association of Cys23Ser with baseline BPND. These findings indicate that a putatively functional HTR2C variant (Ser23) is associated with greater striatal dopamine release during pain in healthy humans. Mesoaccumbal stress sensitivity may mediate the effects of HTR2C variation on risk of neuropsychiatric disorders.

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.

Acceptance into groups and intimate relationships is necessary for survival and emotional well-being. Thus, even everyday occurrences of social rejection (when one is not wanted or liked) can cause sadness, anxiety and social withdrawal. Studies using functional magnetic resonance imaging show that responses to social rejection and physical pain share some common neuronal pathways, leading to a theory of 'social pain'. This theory hypothesizes that the 'pain' of social rejection can be dampened by the endogenous opioids, particularly through the μ-opioid receptor (MOR) which alleviates physical pain, but is also known to regulate responses to social distress in several nonhuman species. To test this hypothesis in humans, we used a MOR radiotracer to measure changes in MOR binding potential (that is, in vivo receptor availability) with positron emission tomography during social feedback. We found that social rejection as well as acceptance activated the MOR system above baseline in different brain regions, showing that the endogenous opioid system responds to social feedback in humans. (a) Social rejection shown here activated the MOR system in the left amygdala. (b) Activation levels extracted from the left amygdala were positively correlated with the personality trait resiliency, suggesting that during rejection high-resilient individuals are more capable of MOR activation, which may be protective or adaptive. For more information on this topic, please refer to the article by Hsu et al. on pages 1211-1217.

No abstract

Neuropeptide Y (NPY) is a neurotransmitter that has been implicated in the development of anxiety and mood disorders. Low levels of NPY have been associated with risk for these disorders, and high levels with resilience. Anxiety and depression are associated with altered intrinsic functional connectivity of brain networks, but the effect of NPY on functional connectivity is not known. Here, we test the hypothesis that individual differences in NPY expression affect resting functional connectivity of the default mode and salience networks. We evaluated static connectivity using graph theoretical techniques and dynamic connectivity with Leading Eigenvector Dynamics Analysis (LEiDA). To increase our power of detecting NPY effects, we genotyped 221 individuals and identified 29 healthy subjects at the extremes of genetically predicted NPY expression (12 high, 17 low). Static connectivity analysis revealed that lower levels of NPY were associated with shorter path lengths, higher global efficiency, higher clustering, higher small-worldness, and average higher node strength within the salience network, whereas subjects with high NPY expression displayed higher modularity and node eccentricity within the salience network. Dynamic connectivity analysis showed that the salience network of low-NPY subjects spent more time in a highly coordinated state relative to high-NPY subjects, and the salience network of high-NPY subjects switched between states more frequently. No group differences were found for static or dynamic connectivity of the default mode network. These findings suggest that genetically driven individual differences in NPY expression influence risk of mood and anxiety disorders by altering the intrinsic functional connectivity of the salience network.