CRF2 Receptor Deficiency Eliminates the Long-Lasting Vulnerability of Motivational States Induced by Opiate Withdrawal.
Neuropsychopharmacol. 2015-02-12; 40(8): 1990-2000
DOI: 10.1038/npp.2015.49
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1. Neuropsychopharmacology. 2015 Jul;40(8):1990-2000. doi: 10.1038/npp.2015.49. Epub
2015 Feb 12.
CRF2 Receptor Deficiency Eliminates the Long-Lasting Vulnerability of
Motivational States Induced by Opiate Withdrawal.
Morisot N(1), Rouibi K(1), Contarino A(1).
Author information:
(1)1] Université Bordeaux, INCIA, UMR 5287, Bordeaux, France [2] CNRS, INCIA, UMR
5287, Bordeaux, France.
Vulnerability to stressful life events is a hallmark of drug dependence that may
persist long after cessation of drug intake and dramatically fuel key clinical
features, such as deregulated up-shifted motivational states and craving.
However, to date, no effective therapy is available for reducing vulnerability to
stressful events in former drug users and drug-dependent patients, mostly because
of poor knowledge of the mechanisms underlying it. In this study, we report that
genetic inactivation of the stress-responsive corticotropin-releasing factor
receptor-2 (CRF2-/-) completely eliminates the reemergence of increased
nonrewarded nose-pokes, reflecting up-shifted motivational states, triggered by
ethological environmental stressors long after cessation of morphine
administration in mice. Accordingly, CRF2 receptor deficiency completely
abolishes the increase in biomarkers of synthesis of major brain motivational
substrates, such as ventral tegmental area (VTA) dopamine (DA) and amygdala
γ-aminobutyric acid (GABA) systems, associated with the stress-induced
reemergence of up-shifted motivational states long after opiate withdrawal.
Nevertheless, neither CRF2 receptor deficiency nor long-term opiate withdrawal
affects amygdala CRF or hypothalamus CRF expression, indicating preserved brain
stress-coping systems. Moreover, CRF2 receptor deficiency does not influence the
locomotor or the anxiety-like effect of long-term opiate withdrawal. Thus, the
present results reveal an essential and specific role for the CRF2 receptor in
the stress-induced reemergence of up-shifted motivational states and related
alterations in brain motivational systems long after opiate withdrawal. These
findings suggest new strategies for the treatment of the severe and long-lasting
vulnerability that inexorably follows drug withdrawal and hinder drug abstinence.
DOI: 10.1038/npp.2015.49
PMCID: PMC4839523
PMID: 25672976 [Indexed for MEDLINE]