The corticotropin-releasing factor receptor-2 mediates the motivational effect of opiate withdrawal

Altered motivational processes are key features of drug dependence and withdrawal, yet their neural mechanisms remain largely unknown. The present study shows that genetic disruption of the corticotropin-releasing factor receptor-2 (CRF2−/−) does not impair motivation for palatable food in drug-naïve mice. However, CRF2 receptor-deficiency effectively reduces the increase in palatable food-driven motivation induced by opiate withdrawal. Indeed, both in male and female wild-type mice, withdrawal from escalating morphine doses (20-100 mg/kg) induces a dramatic and relatively long-lasting (6 days) increase in palatable food-driven operant behavior under a progressive ratio (PR) schedule of reinforcement. In contrast, either male or female morphine-withdrawn CRF2−/− mice show smaller and shorter (2 days) increases in motivation than wild-type mice. Nevertheless, CRF2 receptor-deficiency does not impair the ability to discriminate reinforced behavior prior to, during the partial opiate withdrawal periods occurring between morphine injections and following drug discontinuation, indicating preserved cognitive function. Moreover, CRF2 receptor-deficiency does not affect the ambulatory or body weight effects of intermittent morphine injections and withdrawal. These results provide initial evidence of a gender-independent and specific role for the CRF2 receptor in the motivational effects of opiate withdrawal.