title: Glial cell line-derived neurotrophic factor mediates the desirable actions of the anti-addiction drug ibogaine against alcohol consumption.
abstract: Alcohol addiction manifests as uncontrolled drinking despite negative consequences. Few medications are available to treat the disorder. Anecdotal reports suggest that ibogaine, a natural alkaloid, reverses behaviors associated with addiction including alcoholism; however, because of side effects, ibogaine is not used clinically. In this study, we first characterized the actions of ibogaine on ethanol self-administration in rodents. Ibogaine decreased ethanol intake by rats in two-bottle choice and operant self-administration paradigms. Ibogaine also reduced operant self-administration of ethanol in a relapse model. Next, we identified a molecular mechanism that mediates the desirable activities of ibogaine on ethanol intake. Microinjection of ibogaine into the ventral tegmental area (VTA), but not the substantia nigra, reduced self-administration of ethanol, and systemic administration of ibogaine increased the expression of glial cell line-derived neurotrophic factor (GDNF) in a midbrain region that includes the VTA. In dopaminergic neuron-like SHSY5Y cells, ibogaine treatment upregulated the GDNF pathway as indicated by increases in phosphorylation of the GDNF receptor, Ret, and the downstream kinase, ERK1 (extracellular signal-regulated kinase 1). Finally, the ibogaine-mediated decrease in ethanol self-administration was mimicked by intra-VTA microinjection of GDNF and was reduced by intra-VTA delivery of anti-GDNF neutralizing antibodies. Together, these results suggest that GDNF in the VTA mediates the action of ibogaine on ethanol consumption. These findings highlight the importance of GDNF as a new target for drug development for alcoholism that may mimic the effect of ibogaine against alcohol consumption but avoid the negative side effects.
authors.affiliation: Ernest Gallo Research Center, University of California, San Francisco, Emeryville, California 94608, USA.
authors.forename: Dao-Yao
authors.initials: DY
authors.lastname: He
authors.forename: Nancy N H
authors.initials: NN
authors.lastname: McGough
authors.forename: Ajay
authors.initials: A
authors.lastname: Ravindranathan
authors.forename: Jerome
authors.initials: J
authors.lastname: Jeanblanc
authors.forename: Marian L
authors.initials: ML
authors.lastname: Logrip
authors.forename: Khanhky
authors.initials: K
authors.lastname: Phamluong
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Janak
authors.forename: Dorit
authors.initials: D
authors.lastname: Ron
mesh_terms: D000437:Alcoholism / Q000188:drug therapy / Q000503:physiopathology*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000502:physiology; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D007050:Ibogaine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008845:Microinjections; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D012008:Recurrence; D012646:Self Administration; D013378:Substantia Nigra / Q000187:drug effects; D017557:Ventral Tegmental Area / Q000187:drug effects
chemical_list: C495039:GDNF protein, human; C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D000431:Ethanol; D007050:Ibogaine; D004298:Dopamine