GDNF and alcohol use disorder

Glial cell line‐derived neurotrophic factor (GDNF) has been extensively studied for its role in the development and maintenance of the midbrain dopaminergic system, although evidence suggests that GDNF also plays a role in drug and alcohol addiction. This review focuses on the unique actions of GDNF in the mechanisms that prevent the transition from recreational alcohol use to abuse. Specifically, we describe studies in rodents suggesting that alcohol acutely increases GDNF expression in the ventral tegmental area, which enables the activation of the mitogen‐activated protein kinase signaling pathway and the gating of alcohol intake. We further provide evidence to suggest that GDNF acts in the ventral tegmental area via both nongenomic and genomic mechanisms to suppress alcohol consumption. In addition, we describe findings indicating that when this endogenous protective pathway becomes dysregulated, alcohol intake levels escalate. Finally, we describe the potential use of GDNF inducers as a novel therapeutic approach to treat alcohol use disorder. Glial cell line‐derived neurotrophic factor (GDNF) plays an important role in numerous neuronal functions during development and adulthood. In this review article, we focus on the critical role of GDNF in mechanisms that prevent the development of alcohol use disorder. We describe evidence showing that the endogenous GDNF system acts to maintain low alcohol‐drinking levels. Moreover, increasing GDNF levels in the mesolimbic system suppresses alcohol consumption, relapse, and reward by regulating mesolimbic dopamine activity, highlighting the GDNF system as a possible target for drinking reduction.