Drug repurposing of riluzole attenuates acquisition, accelerates extinction, and prevents reinstatement of ethanol-induced conditioned place preference.

BACKGROUND

Alcohol use disorder (AUD) is associated with persistent drug-related memories that lead to relapse. Glutamatergic dysregulation plays a critical role in the acquisition, extinction, and reinstatement of alcohol. Riluzole, a glutamate-modulating agent, has been suggested to influence these processes; however, its effects on ethanol-related contextual learning are not fully defined.

METHODS

Male Swiss albino mice (25-30 g) were used in a biased conditioned place preference (CPP) model to evaluate the effects of riluzole on ethanol-induced acquisition, extinction and reinstatement in mice. Animals were conditioned with ethanol (2.0 g/kg, i.p). Riluzole (3, 10, or 30 mg/kg, i.p.) was given 30 min before ethanol administration. Extinction and reinstatement phase was conducted by using separate cohort. The ability of riluzole to prevent reinstatement was then assessed using a low priming dose of ethanol (0.5 g/kg, i.p.). CPP was quantified as the time spent in the drug-paired compartment.

RESULTS

Ethanol produced a strong CPP and confirmed the successful acquisition of drug-context associations. Riluzole did not significantly alter acquisition at low doses (3 and 10 mg/kg), but a modest effect was observed at the highest dose (30 mg/kg). During extinction, riluzole facilitated a time-dependent reduction in CPP. Riluzole 10 and 30 mg/kg, increased extinction learning. In the reinstatement phase, ethanol pre-treatment significantly induced CPP, whereas riluzole reduced this effect at 10 and 30 mg/kg and showed no significant reducing effect at 3 mg/kg.

CONCLUSIONS

Riluzole attenuated ethanol-induced CPP, facilitated extinction, and reduced reinstatement in a dose and phase-dependent manner. These findings demonstrate that riluzole influences multiple phases of ethanol-associated conditioned behavior and support its further investigation as a potential pharmacological strategy for alcohol use disorder.