Modafinil blocks reinstatement of extinguished opiate-seeking in rats: Mediation by a glutamate mechanism

Opiate addiction is characterized by high rates of relapse even after long periods of abstinence, requiring new relapse-prevention treatments that do not have abuse potential. Recently, clinical studies suggested that the wake-promoting drug modafinil might decrease relapse in cocaine addicts. In addition, group II metabotropic glutamate receptors (mGlu2/3R) have been suggested as a new therapeutic target for drug addiction. Here, we investigated the ability of modafinil to prevent the acute morphine to promote reinstatement of extinguished preference for morphine, and the involvement of mGlu2/3Rs in this effect. Conditioned place preference (CPP) for morphine was induced in Sprague-Dawley rats, followed by extinction training. Preference for the morphine-paired side was reinstated following extinction by a morphine-priming injection. The results of our study showed that modafinil (300 mg/kg, i.p., but not 100 mg/kg) 30 min before the morphine-priming injection blocked reinstatement of extinguished CPP. The anti-reinstatement effect of modafinil was completely prevented by pretreatment with the selective mGlu2/3 antagonist LY341495. Additional experiments indicated that modafinil alone did not produce a preference, and that modafinil did not alter the expression of morphine CPP or the cueing properties of morphine either 1 or 14 days after morphine CPP conditioning. These data reveal a novel mechanism for modafinil actions, a role for mGlu2/3 receptors in reinstatement of opiate-seeking, and a new therapeutic option to treat relapse in opiate addiction.