Affiliated with Université Laval & CERVO Research Centre

Neuroimmune Regulation of GABAergic Neurons Within the Ventral Tegmental Area During Withdrawal from Chronic Morphine.

TitleNeuroimmune Regulation of GABAergic Neurons Within the Ventral Tegmental Area During Withdrawal from Chronic Morphine.
Publication TypeJournal Article
Year of Publication2016
AuthorsTaylor AMW, Castonguay A, Ghogha A, Vayssiere P, Pradhan AAA, Xue L, Mehrabani S, Wu J, Levitt P, Olmstead MC, De Koninck Y, Evans CJ, Cahill CM
JournalNeuropsychopharmacology
Volume41
Issue4
Pagination949-59
Date Published2016 Mar
ISSN1740-634X
KeywordsAnimals, Brain-Derived Neurotrophic Factor, Cocaine, GABAergic Neurons, Male, Mice, Mice, Inbred C57BL, Microglia, Models, Neurological, Morphine, Neuroimmunomodulation, Reward, Substance Withdrawal Syndrome, Symporters, Ventral Thalamic Nuclei
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.

DOI10.1038/npp.2015.221
Alternate JournalNeuropsychopharmacology
PubMed ID26202104
PubMed Central IDPMC4748420
Grant ListMOP 12942 / / Canadian Institutes of Health Research / Canada
P50 DA005010 / DA / NIDA NIH HHS / United States
R00 DA031243 / DA / NIDA NIH HHS / United States
MOP 123298 / / Canadian Institutes of Health Research / Canada
K99 DA031243 / DA / NIDA NIH HHS / United States