Univ. Bordeaux, INCIA, UMR 5287, F-33000 Bordeaux, France.
Neuropharmacology. 2013 Oct;73:41-7. doi: 10.1016/j.neuropharm.2013.05.011. Epub 2013 May 21.
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 In contrast, either male or female morphine-withdrawn CRF₂-/- mice show smaller and shorter (2 days) increases in motivation than wild-type mice.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.
动机过程的改变是药物依赖和戒断的主要特征，但它们的神经机制在很大程度上仍然未知。本研究表明，在没有药物的情况下，CRF₂ 受体缺失不会损害对美味食物的动机。然而，CRF₂ 受体缺失有效地减少了阿片类药物戒断引起的美味食物驱动动机的增加。事实上，无论是雄性还是雌性野生型小鼠，从递增剂量的吗啡（20-100mg/kg）戒断中，在递增比率（PR）强化方案下，都会引起美味食物驱动操作性行为的剧烈且相对持久（6 天）增加。相比之下，吗啡戒断的 CRF₂-/- 雄性或雌性小鼠的动机增加幅度较小且持续时间较短（2 天）。然而，CRF₂ 受体缺失并不影响在吗啡注射之间和药物停止后发生的部分阿片类药物戒断期间，对强化行为进行区分的能力，表明认知功能正常。此外，CRF₂ 受体缺失不影响间歇性吗啡注射和戒断时的活动或体重变化。这些结果初步证明了 CRF₂ 受体在阿片类药物戒断的动机效应中具有性别独立和特定的作用。
