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

Br J Pharmacol. 2018 May;175(9):1504-1518. doi: 10.1111/bph.14159. Epub 2018 Mar 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arginine Vasopressin / biosynthesis
  • Cocaine / adverse effects*
  • Corticotropin-Releasing Hormone
  • Exploratory Behavior
  • Hypothalamus / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Oxytocin / biosynthesis
  • Receptors, Corticotropin-Releasing Hormone / deficiency*
  • Receptors, Corticotropin-Releasing Hormone / genetics
  • Social Behavior*
  • Stress, Psychological / metabolism
  • Stress, Psychological / psychology*
  • Substance Withdrawal Syndrome / metabolism
  • Substance Withdrawal Syndrome / psychology*

Substances

  • Receptors, Corticotropin-Releasing Hormone
  • Arginine Vasopressin
  • Oxytocin
  • Corticotropin-Releasing Hormone
  • Cocaine