title: Activation of serotonin 5-HT(2C) receptor suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in morphine-dependent mice.
abstract: Opioid abuse and dependence have evolved into an international epidemic as a significant clinical and societal problem with devastating consequences. Repeated exposure to the opioid, for example morphine, can induce profound, long-lasting behavioral sensitization and physical dependence, which are thought to reflect neuroplasticity in neural circuitry. Central serotonin (5-HT) neurotransmission participates in the development of dependence on and the expression of withdrawal from morphine. Serotonin 5-HT(2C) receptor (5-HT(2C)R) agonists suppress psychostimulant nicotine or cocaine-induced behavioral sensitization and drug-seeking behavior; however, the impact of 5-HT(2C)R agonists on behaviors relevant to opioid abuse and dependence has not been reported. In the present study, the effects of 5-HT(2C)R activation on the behavioral sensitization and naloxone-precipitated withdrawal symptoms were examined in mice underwent repeated exposure to morphine. Male mice received morphine (10 mg/kg, s.c.) to develop behavioral sensitization. Lorcaserin, a 5-HT(2C)R agonist, prevented the induction and expression, but not the development, of morphine-induced behavioral sensitization. Another cohort of mice received increasing doses of morphine over a 7-day period to induce morphine-dependence. Pretreatment of lorcaserin, or the positive control clonidine (an alpha 2-adrenoceptor agonist), ameliorated the naloxone-precipitated withdrawal symptoms. SB 242084, a selective 5-HT(2C)R antagonist, prevented the lorcaserin-mediated suppression of behavioral sensitization and withdrawal. Chronic morphine treatment was associated with an increase in the expression of 5-HT(2C)R protein in the ventral tegmental area, locus coeruleus and nucleus accumbens. These findings suggest that 5-HT(2C)R can modulate behavioral sensitization and withdrawal in morphine-dependent mice, and the activation of 5-HT(2C)R may represent a new avenue for the treatment of opioid addiction.
authors.affiliation: School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China; Life Science Initiative, Charles E. Schmidt College of Science, Florida Atlantic University, 5353 Parkside Drive, Jupiter, FL 33458, USA. Electronic address: gzhang@fau.edu.
authors.forename: Gongliang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Wu
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, College of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
authors.forename: Yong-Mei
authors.initials: YM
authors.lastname: Zhang
authors.affiliation: School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Liu
authors.affiliation: School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Pang
authors.affiliation: College of Medicine, Anhui University of Science & Technology, 25 Dongshan Middle Road, Huainan, Anhui 232001, China.
authors.forename: Xinrong
authors.initials: X
authors.lastname: Tao
authors.affiliation: School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China.
authors.forename: Liuyi
authors.initials: L
authors.lastname: Dong
authors.affiliation: Life Science Initiative, Charles E. Schmidt College of Science, Florida Atlantic University, 5353 Parkside Drive, Jupiter, FL 33458, USA. Electronic address: rstackma@fau.edu.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Stackman
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000633:toxicity; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007211:Indoles / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009020:Morphine / Q000633:toxicity; D009021:Morphine Dependence / Q000150:complications*; D009270:Naloxone / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000627:therapeutic use*; D011930:Reaction Time / Q000187:drug effects; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000209:etiology*; D013997:Time Factors
chemical_list: C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; D000701:Analgesics, Opioid; D001552:Benzazepines; D007211:Indoles; D009292:Narcotic Antagonists; D044405:Receptor, Serotonin, 5-HT2C; D012702:Serotonin Antagonists; D009270:Naloxone; C506658:lorcaserin; D009020:Morphine
keywords: 5-HT(2C) receptor; Behavioral sensitization; Locus coeruleus; Morphine; Nucleus accumbens; Serotonin; Ventral tegmental area; Withdrawal