title: Agmatine Prevents Adaptation of the Hippocampal Glutamate System in Chronic Morphine-Treated Rats.
abstract: Chronic exposure to opioids induces adaptation of glutamate neurotransmission, which plays a crucial role in addiction. Our previous studies revealed that agmatine attenuates opioid addiction and prevents the adaptation of glutamate neurotransmission in the nucleus accumbens of chronic morphine-treated rats. The hippocampus is important for drug addiction; however, whether adaptation of glutamate neurotransmission is modulated by agmatine in the hippocampus remains unknown. Here, we found that continuous pretreatment of rats with ascending doses of morphine for 5 days resulted in an increase in the hippocampal extracellular glutamate level induced by naloxone (2 mg/kg, i.p.) precipitation. Agmatine (20 mg/kg, s.c.) administered concurrently with morphine for 5 days attenuated the elevation of extracellular glutamate levels induced by naloxone precipitation. Furthermore, in the hippocampal synaptosome model, agmatine decreased the release and increased the uptake of glutamate in synaptosomes from chronic morphine-treated rats, which might contribute to the reduced elevation of glutamate levels induced by agmatine. We also found that expression of the hippocampal NR2B subunit, rather than the NR1 subunit, of N-methyl-D-aspartate receptors (NMDARs) was down-regulated after chronic morphine treatment, and agmatine inhibited this reduction. Taken together, agmatine prevented the adaptation of the hippocampal glutamate system caused by chronic exposure to morphine, including modulating extracellular glutamate concentration and NMDAR expression, which might be one of the mechanisms underlying the attenuation of opioid addiction by agmatine.
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
authors.forename: Tai-Yun
authors.initials: TY
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
authors.forename: Rui-Bin
authors.initials: RB
authors.lastname: Su
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China. wuning7671@126.com.
authors.forename: Ning
authors.initials: N
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China. jinli9802@163.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects; D000376:Agmatine / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D004347:Drug Interactions; D055664:Electrochemical Techniques; D045604:Extracellular Fluid / Q000187:drug effects* / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013997:Time Factors
chemical_list: C121001:NR2B NMDA receptor; D009292:Narcotic Antagonists; D009294:Narcotics; D016194:Receptors, N-Methyl-D-Aspartate; D009270:Naloxone; D018698:Glutamic Acid; D000376:Agmatine; D009020:Morphine
keywords: Agmatine; Extracellular glutamate; Hippocampus; NMDA receptors; Opioid addiction