title: BDNF signaling in the VTA links the drug-dependent state to drug withdrawal aversions.
abstract: Drug administration to avoid unpleasant drug withdrawal symptoms has been hypothesized to be a crucial factor that leads to compulsive drug-taking behavior. However, the neural relationship between the aversive motivational state produced by drug withdrawal and the development of the drug-dependent state still remains elusive. It has been observed that chronic exposure to drugs of abuse increases brain-derived neurotrophic factor (BDNF) levels in ventral tegmental area (VTA) neurons. In particular, BDNF expression is dramatically increased during drug withdrawal, which would suggest a direct connection between the aversive state of withdrawal and BDNF-induced neuronal plasticity. Using lentivirus-mediated gene transfer to locally knock down the expression of the BDNF receptor tropomyosin-receptor-kinase type B in rats and mice, we observed that chronic opiate administration activates BDNF-related neuronal plasticity in the VTA that is necessary for both the establishment of an opiate-dependent state and aversive withdrawal motivation. Our findings highlight the importance of a bivalent, plastic mechanism that drives the negative reinforcement underlying addiction.
authors.affiliation: Department of Molecular Genetics, Neurobiology Research Group, University of Toronto, Toronto, Ontario, M5S3E1 Canada, vargashector@yahoo.com.
authors.forename: Hector
authors.initials: H
authors.lastname: Vargas-Perez
authors.affiliation: Department of Anatomy, Faculty of Medicine and Health Sciences, United Arab Emirates University, Alabama Ain, 17666 United Arab Emirates.
authors.forename: Amine
authors.initials: A
authors.lastname: Bahi
authors.affiliation: Department of Medical Biophysics, Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, M5S3E1 Canada.
authors.forename: Mary Rose
authors.initials: MR
authors.lastname: Bufalino
authors.affiliation: Department of Molecular Genetics, Neurobiology Research Group, University of Toronto, Toronto, Ontario, M5S3E1 Canada.
authors.forename: Ryan
authors.initials: R
authors.lastname: Ting-A-Kee
authors.affiliation: Department of Molecular Genetics, Neurobiology Research Group, University of Toronto, Toronto, Ontario, M5S3E1 Canada.
authors.forename: Geith
authors.initials: G
authors.lastname: Maal-Bared
authors.affiliation: Department of Molecular Genetics, Neurobiology Research Group, University of Toronto, Toronto, Ontario, M5S3E1 Canada.
authors.forename: Jenny
authors.initials: J
authors.lastname: Lam
authors.affiliation: Department of Molecular Genetics, Neurobiology Research Group, University of Toronto, Toronto, Ontario, M5S3E1 Canada.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Fahmy
authors.affiliation: Department of Molecular Genetics, Neurobiology Research Group, University of Toronto, Toronto, Ontario, M5S3E1 Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Clarke
authors.affiliation: Department of Psychology and Center for Neuroscience, Brigham Young University, Provo, UT 84602, and.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Blanchard
authors.affiliation: Department of Psychology and Center for Neuroscience, Brigham Young University, Provo, UT 84602, and.
authors.forename: Brett R
authors.initials: BR
authors.lastname: Larsen
authors.affiliation: Department of Psychology and Center for Neuroscience, Brigham Young University, Provo, UT 84602, and.
authors.forename: Scott
authors.initials: S
authors.lastname: Steffensen
authors.affiliation: Department of Medicine, Division of Biochemistry, University of Fribourg, Fribourg 1700, Switzerland.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Dreyer
authors.affiliation: Department of Molecular Genetics, Neurobiology Research Group, University of Toronto, Toronto, Ontario, M5S3E1 Canada, Department of Medical Biophysics, Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, M5S3E1 Canada.
authors.forename: Derek
authors.initials: D
authors.lastname: van der Kooy
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000235:genetics; D003932:Heroin / Q000008:administration & dosage / Q000009:adverse effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009294:Narcotics / Q000008:administration & dosage / Q000009:adverse effects; D009293:Opioid-Related Disorders / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000473:pathology*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009294:Narcotics; D003932:Heroin; D005968:Glutamate Decarboxylase
keywords: BDNF; TrkB; dependent state; drug addiction; opiates; withdrawal