Relapse to drug-seeking after abstinence is the most challenging problem in treating drug addiction. Therefore, the demand for anti-relapse medications is high. Clinical trials have reported that modafinil, a wake-promoting agent used to treat sleep disorders such as narcolepsy, is effective in treating cocaine dependence. Although a weak stimulant, sites of action and behavioral effects of modafinil appear to be different from those of cocaine or amphetamine. Modafinil blunts the reinforcing as well as cardiovascular effects of cocaine. More importantly, modafinil decreases cocaine use and relapse rates in cocaine addicts (Dackis et al, 2005; Hart et al, 2008). Larger multi-center clinical trials of modafinil have found modestly positive outcomes (Anderson et al, 2009). In addition, modafinil showed promise in a small group of methamphetamine-dependent subjects and in pathological gamblers with high impulsivity. However, it appears that modafinil may only be effective in cocaine addicts without alcohol dependence (Anderson et al, 2009). Modafinil also is reported to increase negative affect and withdrawal symptoms associated with nicotine dependence. These findings indicate consideration of smoking and alcohol abuse in using modafinil as an anti-relapse medication.

Despite clinical uses of modafinil, its mechanism(s) of action is still unclear. Using an animal model of relapse, we recently found that modafinil blocked reinstatement of an extinguished morphine conditioned place preference (CPP) in rats, extending the anti-relapse properties of modafinil to opiates (Tahsili-Fahadan et al, 2008). This anti-relapse effect of modafinil was blocked by administering an mGluR2/3 receptor antagonist, LY341495 (Figure 1), which is in line with previous findings, indicating the involvement of mGlu2/3 receptors in treatments for opiate and cocaine reinstatement in animal studies (Kalivas, 2009). This finding leads us to hypothesize that modafinil may block opiate relapse by stimulating mGlu2/3 receptors, effectively replacing the depleted tonic glutamate reservoir in the brain induced by chronic exposure to drugs of abuse, thereby preventing relapse to drug-seeking/taking (Kalivas, 2009).

Figure 1
figure 1

mGlu2/3 receptor blockade prevents the anti-relapse effects of modafinil. Rats were trained for conditoned place preference (CPP) with morphine (8 mg/kg) in a six-session conditioning protocol over 3 consecutive days. Animals were then exposed to extinction training, consisting of two daily 15-min preference tests without any treatment until the relative preference for the morphine-paired side decreased to <+75 s/15 min for four consecutive sessions. The reinstatement test (15 min) was conducted 24 h later. For the reinstatement test, animals received vehicle (left bar) or modafinil (300 mg/kg, i.p.; middle bar) 30 min before a priming injection of morphine (8 mg/kg) followed immediately by the preference test. Another group (right bar) was also pretreated with the mGlu2/3R antagonist LY341495 30 min before modafinil administration. Injection of LY341495 (3 mg/kg) completely reversed the anti-relapse effects of modafinil on morphine CPP. ###p<0.001 different from the control vehicle group (left bar) and ***p<0.001 different from the modafinil 300 mg/kg+morphine 8 mg/kg group (middle bar); there was no significant difference between the LY341495+modafinil 300 mg/kg+morphine 8 mg/kg group and the morphine 8 mg/kg control group (left bar).

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In addition to this possible glutamate-mediated mechanism, modafinil is reported to affect other neurotransmitter systems such as catecholamines, serotonin, GABA, orexin, and histamine. The mild stimulant properties of modafinil may also be involved in its ability to reduce withdrawal symptoms of stimulant abuse. In a recent human PET study, modafinil was shown to block DA transporters and increase dopamine in the human brain including the nucleus accumbens (Volkow et al, 2009), in line with previous animal data. These and other findings highlight a potential for abuse of modafinil, although available data suggest a much lower potential for abuse and dependency than amphetamine-like stimulants (Myrick et al, 2004).

Altogether, modafinil shows promise as an anti-relapse medication. Nonetheless, its abuse potential and exact mechanism of action warrants further clinical and preclinical investigations.