Involvement of AMPA receptor-mTOR activation in the reinforcing effect of ketamine

抄録

Backgroud: Ketamine addiction has been associated with NMDA receptor hypofunction. However, the downstream signal for the reinforcing effect of ketamine remains unclear. The rapid and potent antidepressant effects of ketamine has been linked to the AMPA receptor activation and mammalian target of rapamycin (mTOR) pathway. The present study explored the effects of rapamycin, a mTOR inhibitor, and perampanel, a selective non-competitive AMPA receptor antagonist, on the reinforcing efficacy of ketamine. Furthermore, AMPA receptor and mTOR have shown to be involved in reinstated drug seeking and excessive drug intake. The effects of rapamycin on reinstatement of ketamine seeking behavior were also examined.

Methods: Male Sprague-Dawley rats were trained to ketamine (0.5 mg/kg) intravenous SA under the fixed ratio (FR) 1 and 2 schedules. Once stable SA was established, administration of rapamycin and perampanel by oral gavage individually 30 min prior to a progressive ratio (PR) schedule. In addition, following extinction rapamycin was given 30 min prior to reinstatement of ketamine seeking induced by cue-, ketamine priming and foot shock.

Results: Both Rapamycin and perampanel significantly reduced the breaking points for ketamine SA and rapamycin effectively prevented the cue-, drug- and stress-induced ketamine reinstatement.

Conclusion: These findings revealed that rapamycin and perampanel reduced the reinforcing efficacy of ketamine and rapamycin prevented the reinstatement of ketamine-seeking behavior, suggesting that AMPAR-mTOR signal play a critical role in ketamine addiction.