Abstract
BackgroundExtinction period of positive affective memory of drug taking and negative affective memory of drug withdrawal, as well as the different response of men and women might be important for the clinical treatment of drug addiction. We investigate the role of corticotropin releasing factor receptor type one (CRF1R) and the different response of male and female mice in the expression and extinction of the aversive memory.Methodology/Principal FindingWe used genetically engineered male and female mice lacking functional CRF1R. The animals were rendered dependent on morphine by intraperitoneally injection of increasing doses of morphine (10–60 mg/kg). Negative state associated with naloxone (1 mg/kg s.c.)-precipitated morphine withdrawal was examined by using conditioned place aversion (CPA) paradigm. No sex differences for CPA expression were found in wild-type (n = 29) or CRF1R knockout (KO) mice (n = 29). However, CRF1R KO mice presented less aversion score than wild-type mice, suggesting that CRF1R KO mice were less responsive than wild-type to continuous associations between drug administration and environmental stimuli. In addition, CPA extinction was delayed in wild-type and CRF1R KO male mice compared with females of both genotypes. The genetic disruption of the CRF1R pathway decreased the period of extinction in males and females suggesting that CRF/CRF1R is implicated in the duration of aversive memory. Our results also showed that the increase in adrenocorticotropic hormone (ACTH) levels observed in wild-type (n = 11) mice after CPA expression, were attenuated in CRF1R KO mice (n = 10). In addition, ACTH returned to the baseline levels in males and females once CPA extinction was finished.Conclusion/SignificanceThese results suggest that, at least, CPA expression is partially due to an increase in plasma ACTH levels, through activation of CRF1R, which can return when CPA extinction is finished.
Highlights
A growing body of evidence indicates that there are differences between men and women in the vulnerability to drug abuse [1]
Our results showed that the increase in adrenocorticotropic hormone (ACTH) levels observed in wild-type (n = 11) mice after conditioned place aversion (CPA) expression, were attenuated in CRF1R KO mice (n = 10)
Present results are in agreement with previous studies [19] which demonstrated that genetic disruption of the CRF/CRF1R circuitry did not affect the reduction of body weight gain induced by escalating morphine doses
Summary
A growing body of evidence indicates that there are differences between men and women in the vulnerability to drug abuse [1]. While there are abundant findings indicating that females are more motivated than males during several phases of drug addiction [2,3,4,5]; there are limited data regarding sex differences in the emotional signs of withdrawal from drugs of abuse. The induction of the acoustic startle reflex and conditioned place aversion (CPA) has been used to assess the emotional component of opioid withdrawal [13]. These animal models mimic the behaviors of the negative affective component of the withdrawal syndrome. There is increasing evidence suggesting sex differences in behavioral response to drug of abuse, the mechanism underlying these differences is currently not well understood, it is important to guide the treatment strategy for men and women. We investigate the role of corticotropin releasing factor receptor type one (CRF1R) and the different response of male and female mice in the expression and extinction of the aversive memory.
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