title: Neuroimmune Regulation of GABAergic Neurons Within the Ventral Tegmental Area During Withdrawal from Chronic Morphine.
abstract: Opioid dependence is accompanied by neuroplastic changes in reward circuitry leading to a negative affective state contributing to addictive behaviors and risk of relapse. The current study presents a neuroimmune mechanism through which chronic opioids disrupt the ventral tegmental area (VTA) dopaminergic circuitry that contributes to impaired reward behavior. Opioid dependence was induced in rodents by treatment with escalating doses of morphine. Microglial activation was observed in the VTA following spontaneous withdrawal from chronic morphine treatment. Opioid-induced microglial activation resulted in an increase in brain-derived neurotrophic factor (BDNF) expression and a reduction in the expression and function of the K(+)Cl(-) co-transporter KCC2 within VTA GABAergic neurons. Inhibition of microglial activation or interfering with BDNF signaling prevented the loss of Cl(-) extrusion capacity and restored the rewarding effects of cocaine in opioid-dependent animals. Consistent with a microglial-derived BDNF-induced disruption of reward, intra-VTA injection of BDNF or a KCC2 inhibitor resulted in a loss of cocaine-induced place preference in opioid-naïve animals. The loss of the extracellular Cl(-) gradient undermines GABAA-mediated inhibition, and represents a mechanism by which chronic opioid treatments can result in blunted reward circuitry. This study directly implicates microglial-derived BDNF as a negative regulator of reward in opioid-dependent states, identifying new therapeutic targets for opiate addictive behaviors.
authors.affiliation: Department of Anesthesiology and Perioperative Care, University of California, Irvine, CA, USA.|Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
authors.forename: Anna M W
authors.initials: AM
authors.lastname: Taylor
authors.affiliation: Institut Universitaire en Santé Mentale de Québec, Québec, QC, Canada.|Department of Psychiatry and Neuroscience, Université Laval, Québec, QC, Canada.
authors.forename: Annie
authors.initials: A
authors.lastname: Castonguay
authors.affiliation: Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
authors.forename: Atefeh
authors.initials: A
authors.lastname: Ghogha
authors.affiliation: Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
authors.forename: Pia
authors.initials: P
authors.lastname: Vayssiere
authors.affiliation: Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
authors.forename: Amynah A A
authors.initials: AA
authors.lastname: Pradhan
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
authors.forename: Lihua
authors.initials: L
authors.lastname: Xue
authors.affiliation: Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
authors.forename: Sadaf
authors.initials: S
authors.lastname: Mehrabani
authors.affiliation: Children's Hospital Los Angeles and the Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
authors.forename: Juli
authors.initials: J
authors.lastname: Wu
authors.affiliation: Children's Hospital Los Angeles and the Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
authors.forename: Pat
authors.initials: P
authors.lastname: Levitt
authors.affiliation: Department of Psychology, Queen's University, Kingston, ON, Canada.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Olmstead
authors.affiliation: Institut Universitaire en Santé Mentale de Québec, Québec, QC, Canada.|Department of Psychiatry and Neuroscience, Université Laval, Québec, QC, Canada.
authors.forename: Yves
authors.identifier: http://orcid.org/0000-0002-5779-9330
authors.initials: Y
authors.lastname: De Koninck
authors.affiliation: Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Evans
authors.affiliation: Department of Anesthesiology and Perioperative Care, University of California, Irvine, CA, USA.|Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Cahill
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage*; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D008959:Models, Neurological; D009020:Morphine / Q000008:administration & dosage*; D015213:Neuroimmunomodulation; D012201:Reward; D013375:Substance Withdrawal Syndrome / Q000276:immunology*; D027981:Symporters / Q000378:metabolism; D020651:Ventral Thalamic Nuclei / Q000187:drug effects / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D003042:Cocaine; D009020:Morphine; D027981:Symporters; D000096922:K Cl- Cotransporters