The past two decades have seen an explosion of research into the molecular and cellular underpinnings of addiction, with preclinical studies providing evidence that disordered reward processing and decision-making due to altered function of myriad pathways in the medial prefrontal cortex (mPFC) plays a key role in addiction-related behaviors, including alcohol use disorder [1]. However, it is also clear that the neural substrates of various addictions, from drugs to food to sex, are overlapping, and that the pathways that underlie these pathologies are not exclusive to addictive disorders but rather resemble the intersection of circuits that process reward, emotion, memory, and other essential functions [2]. Directly targeting molecular pathways central to the ability of the mPFC to process reward, or to seek rewarding stimuli, in order to treat addiction is thus likely to adversely affect non-pathological behaviors, such as appropriate eating for the drug addict or the normal sex life of the gambling addict. It is therefore critical to uncover the molecular mechanisms unique to the behavioral antecedents of addiction, potentially allowing targeted treatment of alcohol use disorder with reduced untoward effects on the unrelated behaviors of the patient.

In the current issue of Neuropsychopharmacology, van der Vaart and colleagues [3] characterize a novel role for mPFC activity of glycogen synthase kinase 3-beta (Gsk3b) in the reinstatement of ethanol seeking—an established model of drug seeking behavior that mirrors drug seeking observed in clinical addiction. Critically, they demonstrate that this role is specific to ethanol relapse, with no effect on relapse to sucrose seeking. The study finds that mPFC GSK3β phosphorylation is increased by acute ethanol exposure, and that AAV-mediated overexpression of GSK3β in mPFC of mice increases ethanol consumption and preference. The authors go on to demonstrate that in rats, operant intake of both ethanol and sucrose is reduced by systemic inhibition of GSK3β, but that subsequent relapse to ethanol seeking after prolonged withdrawal is reduced by systemic GSK3β inhibition while relapse to sucrose seeking is unaffected.

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