High rates of relapse to drug taking are often triggered by exposure to drug-associated cues or drugs of abuse, and they present a major obstacle for the successful treatment of drug addiction (O’Brien, 2005). Despite years of intensive research efforts to date, there is a paucity of effective medications to treat relapse. A core principle behind discovering potentially effective drugs to reduce relapse has been to identify pharmacological compounds that reverse drug-induced changes in the brain, in particular those areas implicated in motivation and reward, such as the medial prefrontal cortex (mPFC) and nucleus accumbens. A plethora of pre-clinical studies from the last 10–15 years have revealed that repeated cocaine exposure produces abnormalities in intrinsic neuronal excitability, glutamatergic synaptic plasticity, and glutamate uptake, in the mPFC and accumbens (Kalivas and Kalivas, 2016; Kourrich et al, 2015). Thus, it would be highly desirable for an anti-relapse compound to renormalize these types of widespread drug-induced changes. Moreover, a compound with a known safety record that has already passed clinical trials and existing on the market would greatly enhance its desirability.

In this issue of Neuropsychopharmacology, Sepulveda-Orengo et al, 2017 investigated whether Riluzole, a compound that is currently in use for treating amyotrophic lateral sclerosis (Traynor et al, 2006), could renormalize these types of adaptations and prevent the reinstatement of cue-induced and cocaine-primed cocaine-seeking. The authors took advantage of this compound because of its multi-target directed action to (1) block action potential (AP) initiation via inhibiting voltage-gated Na+ channels (Cheah et al, 2010); (2) increase expression and activity of glutamate transporters (Brothers et al, 2013); and (3) inhibit synaptic glutamate release via Ca+2 channel inhibition (Cheah et al, 2010). Initially, the authors repeatedly administered Riluzole during extinction learning (before each extinction session) and before the reinstatement test, which attenuated reinstatement of cue- and cocaine-primed cocaine seeking. This effect was not due to any locomotor inactivating effects of the compound, as repeated Riluzole administration did not attenuate the reinstatement of cue-induced sucrose seeking nor general locomotor activity.

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