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Alcohol dependence (AD) frequently co-occurs with major depressive disorder (MDD). While this comorbidity is associated with an increase in disease burden, worse treatment outcomes, and greater economic costs, the underlying neurobiology remains poorly understood. A recent large-scale GWAS of MDD has identified a locus in the TMEM161B-MEF2C region (rs10514299) as a novel risk variant; however, the biological relevance of this variant has not yet been studied. Given previous reports of disrupted reward processing in both AD and MDD, we hypothesized that rs10514299 would be associated with differences in striatal BOLD responses during reward/loss anticipation in AD. DNA samples from 45 recently detoxified patients with AD and 45 healthy controls (HC) were genotyped for rs10514299. Participants performed the Monetary Incentive Delay task in a 3-Tesla MRI scanner. Effects of rs10514299 on striatal activation during anticipation of high/low reward/loss were investigated. Furthermore, we examined associations between rs10514299 and lifetime AD diagnosis in two independent clinical samples [NIAAA: n = 1858 (1123 cases, 735 controls); SAGE: n = 3838 (1848 cases, 1990 controls)], as well as its association with depression severity in a subsample of individuals with a lifetime AD diagnosis (n = 953). Patients carrying the T allele showed significantly greater putamen activation during anticipation of high reward (p = 0.014), low reward (at trend-level; p = 0.081), high loss (p = 0.024), and low loss (p = 0.046) compared to HCs. Association analyses in the NIAAA sample showed a trend-level relationship between rs10514299 and a lifetime AD diagnosis in the European American subgroup (odds ratio = 0.82, p = 0.09). This finding was not replicated in the SAGE sample. In the NIAAA sample, the T allele was significantly associated with greater depression symptom severity in individuals with a lifetime AD diagnosis (β = 1.25, p = 0.02); this association was driven by the African American ancestry subgroup (β = 2.11, p = 0.008). We show for the first time that the previously identified MDD risk variant rs10514299 in TMEM161B-MEF2C predicts neuronal correlates of reward processing in an AD phenotype, possibly explaining part of the shared pathophysiology and comorbidity between the disorders.

The corticotropin releasing factor (CRF) exerts its effects by acting on its receptors and on the binding protein (CRFBP), and has been implicated in alcohol use disorder (AUD). Therefore, identification of the exact contribution of each protein that mediates CRF effects is necessary to design effective therapeutic strategies for AUD. A series of in vitro/in vivo experiments across different species were performed to define the biological discrete role of CRFBP in AUD. First, to establish the CRFBP role in receptor signaling, we developed a novel chimeric cell-based assay and showed that CFRBP full length can stably be expressed on the plasma membrane. We discovered that only CRFBP(10 kD) fragment is able to potentiate CRF-intracellular Ca2+ release. We provide evidence that CRHBP gene loss increased ethanol consumption in mice. Then, we demonstrate that selective reduction of CRHBP expression in the center nucleus of the amygdala (CeA) decreases ethanol consumption in ethanol-dependent rats. CRFBP amygdalar downregulation, however, does not attenuate yohimbine-induced ethanol self-administration. This effect was associated with decreased hemodynamic brain activity in the CRFBP-downregulated CeA and increased hemodynamic activity in the caudate putamen during yohimbine administration. Finally, in alcohol-dependent patients, genetic variants related to the CRFBP(10 kD) fragment were associated with greater risk for alcoholism and anxiety, while other genetic variants were associated with reduced risk for anxiety. Taken together, our data provide evidence that CRFBP may possess both inhibitory and excitatory roles and may represent a novel pharmacological target for the treatment of AUD.

The hormone glucagon-like peptide-1 (GLP-1) regulates appetite and food intake. GLP-1 receptor (GLP-1R) activation also attenuates the reinforcing properties of alcohol in rodents. The present translational study is based on four human genetic association studies and one preclinical study providing data that support the hypothesis that GLP-1R may have a role in the pathophysiology of alcohol use disorder (AUD). Case–control analysis (N=908) was performed on a sample of individuals enrolled in the National Institute on Alcohol Abuse and Alcoholism (NIAAA) intramural research program. The Study of Addiction: Genetics and Environment (SAGE) sample (N=3803) was used for confirmation purposes. Post hoc analyses were carried out on data from a human laboratory study of intravenous alcohol self-administration (IV-ASA; N=81) in social drinkers and from a functional magnetic resonance imaging study in alcohol-dependent individuals (N=22) subjected to a Monetary Incentive Delay task. In the preclinical study, a GLP-1R agonist was evaluated in a mouse model of alcohol dependence to demonstrate the role of GLP-1R for alcohol consumption. The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P=0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P=0.033). The 168Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward. Finally, GLP-1R agonism significantly reduced alcohol consumption in a mouse model of alcohol dependence. These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD.