A brief summary of the articles appearing in this issue of Biological Psychiatry.

        Mechanisms of Alcohol Consumption: Synaptic Plasticity and Neurocircuitry

        Recent evidence has identified matrix metalloproteinase-9 (MMP-9) as a regulator of synaptic plasticity. Here, Stefaniuk et al. (pages 907–917) provide evidence implicating this enzyme in alcohol consumption. They found that MMP-9 knockout animals are less motivated to consume alcohol and show synaptic loss in the central amygdala and reduced plasticity in projections to this region from the basolateral amygdala. The authors also report pilot data from a group of alcohol-dependent patients and healthy comparison subjects. These data suggest that the T allele of a polymorphism in MMP9, which is associated with increased MMP-9 gene expression, is associated with the risk for alcohol dependence. Together, these studies suggest that the propensity for alcohol use disorders may depend upon the integrity of neuroplasticity within the amygdala, which is regulated in part by MMP-9.
        The brain mechanisms underlying pathological alcohol consumption are complex. In the dorsomedial striatum, the interplay between two sets of dopamine cells, containing either D1 or D2 receptors, and their respective neural circuits (direct and indirect pathways, respectively) helps to set the balance between learning from reward and learning from punishment. Here, Cheng et al. (pages 918–929) show that chronic alcohol drinking in mice increases the excitability of striatal D1-cells and reduces the excitability of striatal D2-cells, which together contribute to excessive alcohol consumption. In contrast, D1-cell inhibition or D2-cell excitation reduced alcohol intake. This study highlights the importance of the balance between D1- and D2-cell activity in modulating the propensity to self-administer alcohol and suggests that treatments might be developed that reset this balance.
        Corticotropin-releasing factor (CRF) modulates binge-like alcohol consumption in mice, yet the neurocircuitry involved remains unclear. Here, Rinker et al. (pages 930–940) demonstrate that blunted alcohol intake stemming from blockade of the CRF1 receptor in the ventral tegmental area (VTA) requires intact CRF2 receptor signaling. Additionally, chemogenetic silencing of a CRF circuit that originates in the bed nucleus of the stria terminalis and terminates in the VTA reduced binge drinking, as did CRF2 receptor activation. Together, these data advance our understanding of the role of CRF receptors within the VTA and the neurocircuitry that modulates binge-like alcohol drinking.

        Nalmefene Reduces Reward Anticipation in Alcohol Dependence

        Nalmefene, an opioid antagonist, was recently approved in Europe for the treatment of alcohol dependence. To further clarify the mechanisms underlying its therapeutic effects, Quelch et al. (pages 941–948) used a randomized, double-blind, crossover design to study the effect of a single dose of nalmefene on the brain’s response during a functional imaging task that assessed reward anticipation in heavy-drinking alcohol-dependent males receiving an alcohol infusion. They report that, compared with placebo, nalmefene is associated with a reduced response in the striatum, a brain region associated with reward. This modulation is consistent with the proposed neurobiological mechanism underlying nalmefene’s efficacy in the treatment of alcoholism.

        Role of Oxytocin in Methamphetamine Abuse

        Oxytocin may have promise as a pharmacotherapy for methamphetamine abuse. It is hypothesized that its therapeutic effects may be mediated by oxytocin receptor signaling in the nucleus accumbens. Using a within-session behavioral-economic paradigm that measures demand for methamphetamine and that predicts relapse to methamphetamine consumption, Cox et al. (pages 949–958) show that oxytocin attenuates methamphetamine seeking similarly in both male and female rats. It had the greatest effects in rats with the highest motivation to seek drug. The authors also found that the nucleus accumbens is both necessary and sufficient for the protective effects of oxytocin.

        Methamphetamine and Nucleus Accumbens Glutamate

        To understand the neurobiology of methamphetamine abuse, Szumlinski et al. (pages 959–970) conducted biochemical studies of both selectively bred and inbred mice varying in their methamphetamine preference/taking. The authors discovered that elevated indices of nucleus accumbens glutamate transmission were associated with the propensity to self-administer methamphetamine. Further, subchronic methamphetamine produced this “hyperglutamatergic state,” suggesting that both genetic and environmental factors contribute to addiction risk.