UCSF

Alcohol abuse affects millions of people worldwide, and there is an alarming lack of efficient treatments for this disease. We previously identified a growth factor, glial cell line-derived neurotrophic factor (GDNF), that acts in the ventral tegmental area (VTA) to reduce alcohol drinking, seeking, and relapse in rodents (Carnicella et al., 2008), suggesting that targeting GDNF and/or its signaling pathway is a potential treatment for alcoholism. I set out to characterize the relationship between alcohol and GDNF, as well as its signaling pathway and its implications for the treatment of alcohol addiction.

Using rodent models, I identify GDNF as a novel alcohol-responsive gene in the VTA. I show that early alcohol drinking induces GDNF expression, which regulates the escalation of excessive drinking. I also demonstrate that after a long history of excessive drinking, GDNF levels are abnormally decreased, possibly contributing to the motivation to continue drinking. I also detail two putative molecular mechanisms involving the Zif268 and Pitx3 transcription factors, which may underlie the alcohol-mediated changes in endogenous GDNF expression in the VTA.

I next outline the identification of protein targets of the GDNF signaling pathway that may mitigate GDNF's anti-alcohol actions. I identify the synaptic vesicle protein, Synapsin I as a novel target of GDNF signaling, which may play a role in dopamine release, consequently affecting alcohol drinking.

Finally, I include the results of a collaborative study in which we demonstrate that pharmacological activation of the GDNF signaling pathway by the FDA-approved drug, cabergoline, effectively lowers alcohol-drinking and -seeking behaviors in rodents. Importantly, cabergoline's actions are due to its ability to up-regulate GDNF, and thus activate its signaling pathway.

Together, these findings document a reciprocal relationship between alcohol and endogenous GDNF expression in the VTA, identify a novel target of GDNF signaling that may play a role in GDNF's anti-alcohol actions, and establish a model in which the targeted pharmacological up-regulation of GDNF can effectively reduce the risk of relapse.

Carnicella S, Kharazia V, Jeanblanc J, Janak PH, Ron D (2008). GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse. PNAS 105:8114-8119.