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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.

Trophic factors have shown great promise in their potential to treat neurological disease. In particular, glial cell line-derived neurotrophic factor (GDNF) has been identified as a potent neurotrophic factor for midbrain dopamine (DA) neurons in the substantia nigra (SN), which lose function in Parkinson’s disease (PD). GDNF progressed to phase II clinical trials, which did not meet proposed endpoints. The large size and binding characteristics of GDNF have been suspected to contribute to some of the shortcomings of GDNF related to delivery to target brain regions. Smaller peptides derived from GDNF (Dopamine-Neuron Stimulating Peptides – DNSPs) have been recently investigated and appear to demonstrate trophic-like effects comparable to GDNF. In the described studies, a time course study was conducted to determine in vivo DA-release characteristics 1-, 2- and 4- weeks after peptide treatment. These studies determined the effects on DA terminals within striatal sub-regions using microelectrodes. A heterogeneous effect on striatal sub-regions was apparent with the maximum effect in the dorsal striatum – corresponding to terminals originating from the SN. Dysregulation of GDNF or GDNF signaling is believed to contribute to motor dysfunction in aging and PD. Thus, it is hypothesized that GDNF is necessary for the maintenance and function of neurons. To extend this line of investigation, in vivo functional measures (DA-release and -uptake) and behavioral and cellular alterations were investigated in a transgenic mouse model (Gdnf+/-) with reduced GDNF protein levels. The described studies determined that both DA-uptake and -release properties were altered in middle-aged Gdnf+/- mice with only modest reductions in DA neurochemical levels. GDNF levels in Gdnf+/- mice were restored to levels comparable to wild-type (WT) counterparts by treatment with GDNF. GDNF protein supplementation led to enhanced motor behavior and increased markers for DA neurons in the SN of Gdnf+/- mice. Gdnf+/- mice appeared to show a heightened sensitivity to GDNF treatment compared to WT counterparts. Overall, this body of work examines novel synthetic peptides with potential to enhance DA-neuron function and expands upon the current understanding of GDNF’s role in the nigrostriatal pathway.