Social defeat disrupts reward learning and potentiates striatal nociceptin/orphanin FQ mRNA in rats

Abstract

Rationale Mood disorders can be triggered by stress and are characterized by deficits in reward processing, including disrupted reward learning (the ability to modulate behavior according to past rewards). Reward learning is regulated by the anterior cingulate cortex (ACC) and striatal circuits, both of which are implicated in the pathophysiology of mood disorders. Objectives Here we assessed in rats the effects of a potent stressor (social defeat) on reward learning and gene expression in the ACC, ventral tegmental area (VTA), and striatum. Methods Adult male Wistar rats were trained on an operant probabilistic reward task (PRT) and then exposed to three days of social defeat before assessment of reward learning. After testing, ACC, VTA, and striatum were dissected and expression of genes previously implicated in stress was assessed. Results Social defeat blunted reward learning (manifested as reduced response bias toward a more frequently rewarded stimulus), and was associated with increased nociceptin/orphanin FQ (N/OFQ) peptide mRNA levels in the striatum and decreased Fos mRNA levels in the VTA. Moreover, N/OFQ peptide and nociceptin receptor mRNA levels in ACC, VTA and striatum were inversely related to reward learning. Conclusions The behavioral findings parallel previous data in humans, suggesting that stress similarly disrupts reward learning in both species. Increased striatal N/OFQ mRNA in stressed rats characterized by impaired reward learning is consistent with accumulating evidence that antagonism of nociceptin receptors, which bind N/OFQ, has antidepressant-like effects. These results raise the possibility that nociceptin systems represent a molecular substrate through which stress produces reward learning deficits in mood disorders.

A systematic review of the role of the nociceptin receptor system in stress, cognition, and reward: relevance to schizophrenia

“…Another recent study demonstrated negative correlations between reward learning and N/OFQ peptide mRNA levels in the cingulate gyrus and with NOPr mRNA levels in the ventral tegmental area 61 . Overall, the results align with the reward system disruptions noted in schizophrenia, in which the existence of deficits is well supported by the literature 3 .…”

“…These differential findings may arise due to species differences, but may also indicate a dynamic role of NOPr modulation of stress reactivity. Social stress (in different forms) increased N/OFQ and NOPr mRNA in the hippocampus, central amygdala, paraventricular nucleus, and in the nucleus accumbens shell 58 – 61 .…”

Chronic Social Stress Leads to Reduced Gustatory Reward Salience and Effort Valuation in Mice

“…However, the SPT is not a test for the dimensions that underlie deficient reward interest in depression, but rather a test for sustained responsiveness during consummatory behavior (Cuthbert and Insel, 2013 ). Tests of reward bias with analogy to the human test described above (Pizzagalli et al, 2005 ) have been developed for rats (Der-Avakian et al, 2013 , 2016 , 2017 ). In one test version, rats are trained to discriminate between two tone stimuli by pressing the specific lever associated with each tone.…”

The Brain, Explained: A Comprehensive Theory of Brain Function

“…In the HT, it is expressed in nuclei promoting aggression (MPOA, VMH and SUM). Social defeat increases STR NOP [Der-Avakian et al, 2017]. Structurally, it is related to DYN, the other OP associated with negative innates.…”