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.
Highlights
Prescription, diversion, and illicit use of opioid therapeutics have emerged as a major problem in recent years (Compton and Volkow, 2006)
The present study provides the first evidence that microgliaderived Brain-derived neurotrophic factor (BDNF) can mediate the blunted DA activity in opioid-dependent and withdrawn states
We show chronic opioid treatment causes dysregulation in transmembrane Cl− homeostasis in GABAergic neurons of the VTA driven by BDNF and activated microglia
Summary
Prescription, diversion, and illicit use of opioid therapeutics have emerged as a major problem in recent years (Compton and Volkow, 2006). Opioid-dependent animals (Koo et al, 2012; Vargas-Perez et al, 2014) Together, these studies indicate that the BDNF- MATERIALS AND METHODS. Mice were made opioid-dependent by twice-daily injections of escalating doses of morphine sulfate (10, 20, 30, 40 mg/kg, intraperitoneal (i.p.); National Institutes on Drug Abuse (NIDA), Bethesda, MD) for 4 days. The effect of ablating microglia in the VTA on cocaine place preference in opioid-naïve and -dependent animals was assessed. Opioid-naïve rats received systemic 7,8-dihydroxyflavone injections (Tocris Bioscience, Bristol, UK, 10 mg/kg, i.p.), a potent trkB agonist, 1 h prior to cocaine conditioning. After a control period of 50 s, the VTA brain punches from opioid-naïve and -dependent mice perfusion solution was switched to artificial cerebral spinal treated with or without minocycline were assayed for BDNF protein content using western blot (Supplementary Material and Methods).
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