Dataset Information

Corticotropin-releasing factor receptor 2-deficiency eliminates social behaviour deficits and vulnerability induced by cocaine.

ABSTRACT:

Background and purpose

Poor social behaviour and vulnerability to stress are major clinical features of stimulant use disorders. The corticotropin-releasing factor (CRF) system mediates stress responses and might underlie substance use disorders; however, its involvement in social impairment induced by stimulant substances remains unknown. CRF signalling is mediated by two receptor types, CRF₁ and CRF₂ . In the present study we investigated the role of the CRF₂ receptor in social behaviour deficits, vulnerability to stress and related brain alterations induced by cocaine administration and withdrawal.

Experimental approach

CRF₂ receptor-deficient (CRF₂ -/-) and littermate wild-type mice were repeatedly tested in the three-chamber task for sociability (i.e. preference for an unfamiliar conspecific vs. an object) and social novelty preference (SNP; i.e. preference for a novel vs. a familiar conspecific) before and after chronic cocaine administration. An in situ hybridization assay was used to assess gene expression of the stress-responsive arginine vasopressin (AVP) and oxytocin (OT) neuropeptides in the hypothalamus.

Key results

CRF₂ receptor deficiency eliminated the sociability deficit induced by cocaine withdrawal. Moreover, CRF₂ -/- mice did not show either the stress-induced sociability deficit or the increased AVP and OT expression associated with long-term cocaine withdrawal, indicating resilience to stress. Throughout, wild-type and CRF₂ -/- mice displayed SNP, suggesting that cocaine withdrawal-induced sociability deficits were not due to impaired detection of social stimuli.

Conclusions and implications

These findings demonstrate a central role for the CRF₂ receptor in social behaviour deficits and biomarkers of vulnerability induced by cocaine withdrawal, suggesting new therapeutic strategies for stimulant use disorders.

SUBMITTER: Morisot N

PROVIDER: S-EPMC5900993 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Environmental stimuli elicit drug craving and relapse in cocaine users by triggering the retrieval of strong cocainerelated contextual memories. Retrieval can also destabilize drug memories, requiring reconsolidation, a protein synthesis-dependent storage process, to maintain memory strength. Corticotropin-releasing factor (CRF) signaling in the basolateral amygdala (BLA) is necessary for cocainememory reconsolidation. We have hypothesized that a critical source of CRF in the BLA is the dorsal raphe nucleus (DR) based on its neurochemistry, anatomical connectivity, and requisite involvement in cocaine-memory reconsolidation. To test this hypothesis, male and female Sprague-Dawley rats received adeno-associated viruses to express Gi-coupled designer receptors exclusively activated by designer drugs (DREADDs) selectively in CRF neurons of the DR and injection cannulae directed at the BLA. The rats were trained to self-administer cocaine in a distinct environmental context then received extinction training in a different context. They were then briefly reexposed to the cocaine-predictive context to destabilize (reactivate) cocaine memories. Intra-BLA infusions of the DREADD agonist deschloroclozapine (DCZ; 0.1 mM, 0.5 μL/hemisphere) after memory reactivation attenuated cocaine-memory strength, relative to vehicle infusion. This was indicated by a selective, DCZ-induced and memory reactivation-dependent decrease in drug-seeking behavior in the cocaine-predictive context in DREADD-expressing males and females at test compared to respective controls. Notably, BLA-projecting DR CRF neurons that exhibited increased c-Fos expression during memory reconsolidation co-expressed glutamatergic and serotonergic neuronal markers. Together, these findings suggest that the DRCRF → BLA circuit is engaged to maintain cocaine-memory strength after memory destabilization, and this phenomenon may be mediated by DR CRF, glutamate, and/or serotonin release in the BLA.

Project description:Stress-related psychiatric disorders are more prevalent in women than men. As hypersecretion of the stress neuromediator, corticotropin-releasing factor (CRF) has been implicated in these disorders, sex differences in CRF sensitivity could underlie this disparity. Hyperarousal is a core symptom that is shared by stress-related disorders and this has been attributed to CRF regulation of the locus ceruleus (LC)-norepinephrine arousal system. We recently identified sex differences in CRF(1) receptor (CRF(1)) signaling and trafficking that render LC neurons of female rats more sensitive to CRF and potentially less able to adapt to excess CRF compared with male rats. The present study used a genetic model of CRF overexpression to test the hypothesis that females would be more vulnerable to LC dysregulation by conditions of excess CRF. In both male and female CRF overexpressing (CRF-OE) mice, the LC was more densely innervated by CRF compared with wild-type controls. Despite the equally dense CRF innervation of the LC in male and female CRF-OE mice, LC discharge rates recorded in slices in vitro were selectively elevated in female CRF-OE mice. Immunoelectron microscopy revealed that this sex difference resulted from differential CRF(1) trafficking. In male CRF-OE mice, CRF(1) immunolabeling was prominent in the cytoplasm of LC neurons, indicative of internalization, a process that would protect cells from excessive CRF. However, in female CRF-OE mice, CRF(1) labeling was more prominent on the plasma membrane, suggesting that the compensatory response of internalization was compromised. Together, the findings suggest that the LC-norepinephrine system of females will be particularly affected by conditions resulting in elevated CRF because of differences in receptor trafficking. As excessive LC activation has been implicated in the arousal components of stress-related psychiatric disorders, this may be a cellular mechanism that contributes to the increased incidence of these disorders in females.