title: Morphine-induced inhibition of Ca2+-dependent d-serine release from astrocytes suppresses excitability of GABAergic neurons in the nucleus accumbens.
abstract: The nucleus accumbens (NAc) plays a critical role in addictive drug-induced behavioral changes. d-serine is present at high levels in the brain and is involved in the regulation of N-methyl-d-aspartate glutamate (NMDA)-dependent synaptic activity. In this study, we aimed to examine the involvement of d-serine in morphine addiction. Morphine decreased the NMDA receptor-mediated excitatory postsynaptic currents and excitability of GABAergic neurons in the NAc, while exogenous d-serine alleviated the effects of morphine. Morphine reduced extracellular d-serine levels in rat NAc or in primary culture of astrocytes through inhibition of intracellular Ca2+signals and blockade of d-serine release from cell vesicles. Morphine induced robust internalization of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate acid receptor (AMPAR) in primary cultured astrocytes. Moreover, administration of exogenous d-serine to rats inhibited the development of locomotor sensitization to morphine, attenuated the morphine-induced potentiation on conditioned place preference and suppressed the morphine-enhanced expression of p-CREB and ΔFosB in the NAc. Overall, our results showed that morphine inhibited d-serine release from astrocytes through modulation of AMPAR-mediated Ca2+influx, and led to the inhibition of postsynaptic excitability of GABAergic neurons in the NAc. This work may provide a new insight into the underlying mechanisms of morphine addiction.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Disorders and The Collaborative Innovation Center for Brain Sciences, College of Pharmaceutical Sciences, Soochow University, China.|College of Medicine, Nantong University, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Disorders and The Collaborative Innovation Center for Brain Sciences, College of Pharmaceutical Sciences, Soochow University, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Disorders and The Collaborative Innovation Center for Brain Sciences, College of Pharmaceutical Sciences, Soochow University, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Guo
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Disorders and The Collaborative Innovation Center for Brain Sciences, College of Pharmaceutical Sciences, Soochow University, China.
authors.forename: Xuechu
authors.initials: X
authors.lastname: Zhen
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D022162:Cytoplasmic Vesicles / Q000187:drug effects / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D059330:GABAergic Neurons / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D012694:Serine / Q000187:drug effects* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000701:Analgesics, Opioid; D017362:Cyclic AMP Response Element-Binding Protein; C483820:Fosb protein, rat; D010750:Phosphoproteins; D016760:Proto-Oncogene Proteins c-fos; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D009020:Morphine
keywords: GABAergic neuron; N-methyl-d-aspartate glutamate receptor; d-serine; morphine addiction; nucleus accumbens