GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse.
Previously, we demonstrated that the action of the natural alkaloid, ibogaine, to reduce alcohol (ethanol) consumption is mediated by the glial cell line-derived neurotrophic factor (GDNF) in the ventral tegmental area (VTA). Here we set out to test the actions of GDNF in the VTA on ethanol-drinking behaviors. We found that GDNF infusion very rapidly and dose-dependently reduced rat ethanol, but not sucrose, operant self-administration. A GDNF-mediated decrease in ethanol consumption was also observed in rats with a history of high voluntary ethanol intake. We found that the action of GDNF on ethanol consumption was specific to the VTA as infusion of the growth factor into the neighboring substantia nigra did not affect operant responses for ethanol. We further show that intra-VTA GDNF administration rapidly activated the MAPK signaling pathway in the VTA and that inhibition of the MAPK pathway in the VTA blocked the reduction of ethanol self-administration by GDNF. Importantly, we demonstrate that GDNF infused into the VTA alters rats' responses in a model of relapse. Specifically, GDNF application blocked reacquisition of ethanol self-administration after extinction. Together, these results suggest that GDNF, via activation of the MAPK pathway, is a fast-acting selective agent to reduce the motivation to consume and seek alcohol.
Carnicella
Sebastien
S
The Ernest Gallo Research Center and Department of Neurology, University of California at San Francisco, Emeryville, CA 94608, USA.
Kharazia
Viktor
V
Jeanblanc
Jerome
J
Janak
Patricia H
PH
Ron
Dorit
D
D000428:Alcohol Drinking / Q000378:metabolism* / Q000517:prevention & control*; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology*; D008297:Male; D008845:Microinjections; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D055502:Secondary Prevention; D012646:Self Administration; D013378:Substantia Nigra / Q000187:drug effects; D013395:Sucrose / Q000008:administration & dosage / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000201:enzymology
D004791:Enzyme Inhibitors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D000431:Ethanol; D013395:Sucrose; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D004298:Dopamine