title: Glial cell line-derived neurotrophic factor (GDNF) is an endogenous protector in the mesolimbic system against excessive alcohol consumption and relapse.
abstract: Moderate social consumption of alcohol is common; however, only a small percentage of individuals transit from social to excessive, uncontrolled alcohol drinking. This suggests the existence of protective mechanisms that prevent the development of alcohol addiction. Here, we tested the hypothesis that the glial cell line-derived neurotrophic factor (GDNF) in the mesolimbic system [e.g. the nucleus accumbens (Acb) and ventral tegmental area (VTA)] is part of such a mechanism. We found that GDNF knockdown, by infecting rat Acb neurons with a small hairpin RNA (shRNA) targeting the GDNF gene, produced a rapid escalation to excessive alcohol consumption and enhanced relapse to alcohol drinking. Conversely, viral-mediated overexpression of the growth factor in the mesolimbic system blocked the escalation from moderate to excessive alcohol drinking. To access the mechanism underlying GDNF's actions, we measured the firing rate of dopaminergic (DAergic) neurons in the VTA after a history of excessive alcohol intake with or without elevating GDNF levels. We found that the spontaneous firing rate of DAergic neurons in the VTA was reduced during alcohol withdrawal and that GDNF reversed this alcohol-induced DA deficiency. Together, our results suggest that endogenous GDNF in the mesolimbic system controls the transition from moderate to excessive alcohol drinking and relapse via reversal of alcohol-dependent neuro-adaptations in DAergic VTA neurons.
authors.affiliation: The Gallo Research Center, University of California, San Francisco, CA, USA.|Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Segev
authors.identifier: http://orcid.org/0000-0002-3143-6777
authors.initials: S
authors.lastname: Barak
authors.affiliation: The Gallo Research Center, University of California, San Francisco, CA, USA.|Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: The Gallo Research Center, University of California, San Francisco, CA, USA.|Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Somayeh
authors.initials: S
authors.lastname: Ahmadiantehrani
authors.affiliation: The Gallo Research Center, University of California, San Francisco, CA, USA.|Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Sami
authors.initials: S
authors.lastname: Ben Hamida
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA, USA.
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Kells
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Forsayeth
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA, USA.
authors.forename: Krystof S
authors.initials: KS
authors.lastname: Bankiewicz
authors.affiliation: The Gallo Research Center, University of California, San Francisco, CA, USA.|Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Dorit
authors.initials: D
authors.lastname: Ron
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000428:Alcohol Drinking / Q000503:physiopathology*; D000818:Animals; D003216:Conditioning, Operant; D059290:Dopaminergic Neurons / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D055785:Gene Knockdown Techniques; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000172:deficiency / Q000502:physiology*; D008032:Limbic System / Q000502:physiology*; D008297:Male; D009714:Nucleus Accumbens / Q000502:physiology*; D020318:Rats, Long-Evans; D012008:Recurrence; D012646:Self Administration; D015854:Up-Regulation / Q000502:physiology; D017557:Ventral Tegmental Area / Q000502:physiology*
chemical_list: C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor
keywords: Alcohol addiction; GDNF; dopamine; nucleus accumbens; relapse; ventral tegmental area