Wnt7a in Mouse Insular Cortex Contributes to Anxiety-like Behavior During Protracted Abstinence from Morphine

Anxiety is considered an important protracted abstinence symptom that can aggravate craving and relapse risk in opioid addicts. Although the insular cortex (IC) has been reported to be a key brain region in mediating emotional and motivational alterations induced by drug consumption and withdrawal, the role of IC in anxiety related to protracted abstinence remains elusive. In this study, we found that: (1) anxiety-like behavior in morphine-dependent mice became significant after 28 days of withdrawal, while their physical symptoms became undetectable. (2) Activated glutamatergic neurons in the medial IC, but not the anterior or posterior IC were significantly increased after 28 days of withdrawal. Bilateral lesion of the medial IC, but not the anterior or posterior IC with ibotenic acid (IBO) alleviated the anxiety-like behavior. (3) Expression of Wnt7a in the medial IC was significantly increased after 28 days of withdrawal, and specific down-regulation of Wnt7a with AAV-shWnt7a also alleviated the anxiety-like behavior. The findings reveal the medial IC is involved in mediating anxiety-like behavior related to morphine protracted abstinence, in which Wnt7a plays a critical role.