A.Contarino et N. Morisot inNeuropharmacology

The CRF1 and the CRF2 receptor mediate recognition memory deficits and vulnerability induced by opiate withdrawal.
Morisot N, Contarino A. Neuropharmacology. 2016 Feb 18;105:500-507. doi: 10.1016/j.neuropharm.2016.02.021

Nadège Morisot est  post-doc  au Dorit Ron’s Lab, Department of Neurology, University of California San Francisco, California, 94158, United States.
Angelo Contarino /Bordeaux University, PhD, Team leader: Stress

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Cognitive deficits associated with opiate addiction and other substance use disorders are thought to contribute to the high risk of relapse characterizing the disease. Stressful life events may also trigger drug craving and promote relapse to opiate intake. A better understanding of the brain substrates underlying cognitive deficits and stress vulnerability during opiate withdrawal may help the development of effective therapy for drug addiction.

In mammalians, stress responses are orchestrated by the corticotropin-releasing factor (CRF) system, through two distinct receptors, CRF1 and CRF2. Extensive literature has shown the critical contribution of the CRF system to drug addiction. Our previous studies in mouse models revealed that the two CRF receptors differentially contribute to opiate addiction-like behaviors such as negative affective-like states and motivational deficits (Contarino and Papaleo, 2005; Ingallinesi et al, 2012; Papaleo et al, 2007; Morisot et al, 2015). In the present study, we tested whether the CRF receptors mediate cognitive deficits during opiate withdrawal. We also investigated the potential role of CRF receptors in the reemergence of cognitive deficits after exposure to a stressful stimulus following protracted opiate withdrawal.

We used the novel object recognition paradigm, a well-established test modeling episodic memory which is one of the most generalized cognitive function impaired during withdrawal across all types of drugs. We showed that chronic morphine treatment induces recognition memory deficits in wild-type mice up to 14 days after drug cessation. We found that CRF1 receptor-deficient mice still display recognition memory deficits 37 days after the last morphine administration. In net contrast, recognition memory is recovered in CRF2 receptor-deficient mice on opiate withdrawal day 7. Our findings reveal that the two known CRF receptors have opposite roles: CRF1 inactivation prevents while CRF2 inactivation promotes the recovery of memory impairment induced by opiate withdrawal.

Then, we determined whether stress exposure could unmask drug-induced cognitive deficits long-time after the apparent recovery of cognitive function. We demonstrate that an ethological, relatively mild, environmental stressor triggers the reemergence of recognition memory deficit in wild-type mice, long after cessation of drug administration. In net contrast, the stress-induced reemergence of recognition memory deficits is completely abolished in CRF1 and CRF2 receptor-deficient mice. The latter result indicate that both the CRF1 and the CRF2 receptor are essential for cognitive vulnerability to stressors in long-term drug-withdrawn subjects.

Thus, our work clearly reveals a critical role for the two known CRF receptors in cognitive impairment and the long-lasting vulnerability to stressors induced by opiate withdrawal. Together with our previous studies, the present results further suggest new strategies to treat drug addiction. Indeed, blocking the activity of CRF receptors (especially of the CRF2) may help cognitive recovery in drug addicts and also reduce vulnerability to stressful life events, which is a hallmark of substance use disorders. We believe indeed that CRF receptor-targeting medications might promote drug abstinence in drug addicts.

Angelo Contarino /Bordeaux University, PhD, Team leader: Stress, affiliated with the lab: Cognitive and Integrative Neuroscience – Aquitaine Institute /