Sex differences between CRF1 receptor deficient mice following naloxone-precipitated morphine withdrawal in a conditioned place aversion paradigm: implication of HPA axis

PLoS One. 2015 Apr 1;10(4):e0121125. doi: 10.1371/journal.pone.0121125. eCollection 2015.


Background: Extinction 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 finding: We 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/significance: These 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenocorticotropic Hormone / blood
  • Animals
  • Body Weight / drug effects
  • Corticosterone / blood
  • Female
  • Genotype
  • Hypothalamo-Hypophyseal System / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Morphine / administration & dosage*
  • Morphine / pharmacology
  • Naloxone / pharmacology*
  • Narcotic Antagonists / pharmacology*
  • Pituitary-Adrenal System / metabolism*
  • Receptors, Corticotropin-Releasing Hormone / deficiency
  • Receptors, Corticotropin-Releasing Hormone / genetics*
  • Receptors, Corticotropin-Releasing Hormone / metabolism
  • Substance Withdrawal Syndrome / metabolism
  • Substance Withdrawal Syndrome / pathology


  • Narcotic Antagonists
  • Receptors, Corticotropin-Releasing Hormone
  • Naloxone
  • CRF receptor type 1
  • Morphine
  • Adrenocorticotropic Hormone
  • Corticosterone

Grant support

This research was supported by grants from the Ministerio de Ciencia e Innovación (Grants SAF/FEDER 2010-17907; 2013-49076-P), Spain, Red de trastornos adictivos (RETICS RD12/0028//0003), Instituto de Salud Carlos III, Spain. Fundación Séneca (15405/PI/10, Región de Murcia, Spain. JAGC was supported by a predoctoral fellowship from Fundación Séneca, Agencia de Ciencia y Tecnología de la Región de Murcia (ref.15519/FPI/10). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.