The corticotropin-releasing factor receptor-1 pathway mediates the negative affective states of opiate withdrawal

The negative affective symptoms of opiate withdrawal powerfully motivate drug-seeking behavior and may trigger relapse to heroin abuse. To date, no medications exist that effectively relieve the negative affective symptoms of opiate withdrawal. The corticotropin-releasing factor (CRF) system has been hypothesized to mediate the motivational effects of drug dependence. The CRF signal is transmitted by two distinct receptors named CRF receptor-1 (CRF 1 ) and CRF 2 . Here we report that genetic disruption of CRF 1 receptor pathways in mice eliminates the negative affective states of opiate withdrawal. In particular, neither CRF 1 receptor heterozygous ( [12pt]{minimal} {amsmath} {wasysym} {amsfonts} {amssymb} {amsbsy} {mathrsfs} {}{-69pt} {document} {equation*}{CRF}₁+/-{equation*}{document} ) nor homozygous ( [12pt]{minimal} {amsmath} {wasysym} {amsfonts} {amssymb} {amsbsy} {mathrsfs} {}{-69pt} {document} {equation*}{CRF}₁-/-{equation*}{document} ) null mutant mice avoided environmental cues repeatedly paired with the early phase of opiate withdrawal. These results were not due to altered associative learning processes because [12pt]{minimal} {amsmath} {wasysym} {amsfonts} {amssymb} {amsbsy} {mathrsfs} {}{-69pt} {document} {equation*}{CRF}₁+/-{equation*}{document} and [12pt]{minimal} {amsmath} {wasysym} {amsfonts} {amssymb} {amsbsy} {mathrsfs} {}{-69pt} {document} {equation*}{CRF}₁-/-{equation*}{document} mice displayed reliable, conditioned place aversions to environmental cues paired with the κ-opioid receptor agonist U-50,488H. We also examined the impact of CRF 1 receptor-deficiency upon opiate withdrawal-induced dynorphin activity in the nucleus accumbens, a brain molecular mechanism thought to underlie the negative affective states of drug withdrawal. Consistent with the behavioral indices, we found that, during the early phase of opiate withdrawal, neither [12pt]{minimal} {amsmath} {wasysym} {amsfonts} {amssymb} {amsbsy} {mathrsfs} {}{-69pt} {document} {equation*}{CRF}₁+/-{equation*}{document} nor [12pt]{minimal} {amsmath} {wasysym} {amsfonts} {amssymb} {amsbsy} {mathrsfs} {}{-69pt} {document} {equation*}{CRF}₁-/-{equation*}{document} showed increased dynorphin mRNA levels in the nucleus accumbens. This study reveals a cardinal role for CRF/CRF 1 receptor pathways in the negative affective states of opiate withdrawal and suggests therapeutic strategies for the treatment of opiate addiction.