CRF2 Receptor Deficiency Eliminates the Long-Lasting Vulnerability of Motivational States Induced by Opiate Withdrawal

Abstract

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 (CRF 2 − / − ) 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, CRF 2 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 upshifted motivational states long after opiate withdrawal. Nevertheless, neither CRF 2 receptor deficiency nor long-term opiate withdrawal affects amygdala CRF or hypothalamus CRF expression, indicating preserved brain stress-coping systems. Moreover, CRF 2 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 CRF 2 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 longlasting vulnerability that inexorably follows drug withdrawal and hinder drug abstinence.

Corticotropin‐releasing factor receptor 2‐deficiency eliminates social behaviour deficits and vulnerability induced by cocaine

“…Indeed, stress exposure is considered a major risk factor for relapse to substance intake in former substance users (Sinha, 2001). Accordingly, laboratory animal studies showed that physical, psychological or pharmacological stressors reinstate substance-seeking behaviour and induce negative affective-like states, even after relatively long periods of substance withdrawal (Shaham et al, 2003;Blatchford et al, 2005;Breese et al, 2005;Morisot et al, 2015). The present results extend to social behaviour the deleterious consequences of substance withdrawal and the associated long-lasting vulnerability to stress.…”

CRF receptor type 1 (but not type 2) located within the amygdala plays a role in the modulation of anxiety in mice exposed to the elevated plus maze

“…In this sense, several evidences points to a role of amygdala CRF 2 receptors of rodents in the modulation of anxiety related to the withdrawal syndrome and the preference for consumption. For example, Morisot et al (2015) revealed that GABA biosynthesis within the amygdala of mice after opiate withdrawal requires functional CRF 2 receptors. Orozco-Cabal et al (2008), using an electrophysiological approach, showed a synergism between D1-like dopamine receptors and CRF 2 receptors in BLA-to-medial prefrontal cortex synaptic transmission in rats subjected to repeated cocaine treatment.…”

Repeated cocaine or methamphetamine treatment alters astrocytic CRF2 and GLAST expression in the ventral midbrain

“…Stress-induced reinstatement following abstinence is a feature of abuse for multiple classes of drugs. While the role of CRF in the VTA has been explored relative to depressants such as morphine and ethanol, [23][24][25] it has also been studied for its role in stress-induced cocaine seeking. 26 The most important source of CRF in the VTA for cocaine reinstatement is likely from neurons in the bed nucleus of the stria terminalis, 27 although other inputs such as the lateral hypothalamic area and paraventricular hypothalamic nucleus could also play a F I G U R E 4 Repeated cocaine and methamphetamine injections increase CRF2 signal and decrease astrocyte number in the VTA and SN.…”