GDNF and alcohol use disorder

Abstract

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.

Keywords: GDNF; addiction; alcohol; ethanol; mesolimbic system; nucleus accumbens; ventral tegmental area.

Figure 1. GDNF signaling in the VTA-NAc system

GDNF produced in the NAc is retrogradely transported by DA neurons to the VTA, where the GDNF receptors Ret and GFRα1 are expressed. Ligation of GDNF to its receptors in the midbrain results in the activation of ERK1/2, which in turn promotes the spontaneous firing of VTA DA neurons. Increase in the firing of DA neurons increases DA release in the NAc.

Figure 2. Use-dependent dysregulation of alcohol-induced GDNF expression and the development of excessive drinking

Initial bouts of alcohol drinking (solid line) result in the upregulation of GDNF expression (dashed line), which acts to limit subsequent intake. Over time, repeated cycles of increasing amounts of alcohol consumption lead to an eventual decrease in the basal level of GDNF (arrowhead), manifesting in abnormally low levels of the neurotrophic factor that are measured during withdrawal periods. A bout of alcohol consumption, while sufficient to restore GDNF expression to its previous basal levels, no longer induces the enhanced level of expression that would effectively curb subsequent drinking.

Figure 3. Alcohol, GDNF and the mesolimbic dopaminergic system

Withdrawal from excessive alcohol consumption or downregulation of GDNF in the NAc results in deficient DAergic function in the mesolimbic system. This deficiency enhances alcohol seeking and intake, and alcohol temporarily alleviates the DA deficiency (Barak, Ahmadiantehrani, Kharazia et al., 2011). Activating the GDNF signaling pathway, either by infusion of rGDNF or by overexpressing GDNF in the mesolimbic system, reverses withdrawal-induced DA deficiency and consequently suppresses alcohol seeking and drinking.