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Rationale: the role that antidepressants play on alcohol consumption is not well understood. Previous studies have reported that treatment with a Selective Serotonin Reuptake Inhibitor (SSRIs) increases alcohol consumption in an animal model of relapse, however it is unknown whether this effect holds for other antidepressants such as the atypical dopamine/norepinephrine reuptake inhibitors (SNDRI). Objectives: the main goal of the present study was to compare the effects of two classes of antidepressants drugs, bupropion (SNDRI) and fluoxetine (SSRI), on alcohol consumption during relapse. Since glutamatergic and endocannabinoid signaling systems plays an important rolein alcohol abuse and relapse, we also evaluated the effects of both antidepressants ontheexpression of the main important genes and proteins of both systems in the prefrontal cortex,a critical brain region in alcohol relapse. Methods: rats were trained to self-administered alcohol. During abstinence, rats received a14d-treatment with vehicle, fluoxetine (10 mg/kg) or bupropion (20 mg/kg), and we evaluatedalcohol consumption during relapse for 3 weeks. Samples of prefrontal cortex were taken toevaluate the mRNA and protein expression of the different components of glutamatergic andendocannabinoid signaling systems. Results: fluoxetine treatment induced a long-lasting increase in alcohol consumption during relapse, an effect that was not observed in the case of bupropion treatment. The observed increases in alcohol consumption were accompanied by distinct alterations in the glutamate and endocannabinoid systems. Conclusions: our results suggest that SSRIs can negatively impact alcohol consumption in relapse while SNDRIs have no effects. The observed increase in alcohol consumption are accompanied by functional alterations in the glutamatergic and endocannabinoid systems. This finding could open new strategies for the treatment of depression in patients with alcohol use disorders., Depto. de Psicobiología y Metodología en Ciencias del Comportamiento, Fac. de Psicología, TRUE, pub