Activation of serotonin 5-HT2C receptor suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in morphine-dependent mice

NEUROPHARMACOLOGY

卷:101

Article

Zhang, Gongliang^1,4  Wu, Xian¹  Zhang, Yong-Mei²  Liu, Huan¹  Jiang, Qin¹  Pang, Gang¹  Tao, Xinrong³  Dong, Liuyi¹  Stackman, Robert W., Jr.⁴ 

[1] Anhui Med Univ, Sch Basic Med Sci, Hefei 230032, Anhui, Peoples R China

[2] Xuzhou Med Coll, Coll Anesthesiol, Jiangsu Prov Key Lab Anesthesiol, Xuzhou 221002, Jiangsu, Peoples R China

[3] Anhui Univ Sci & Technol, Coll Med, Huainan 232001, Anhui, Peoples R China

[4] Florida Atlantic Univ, Charles E Schmidt Coll Sci, Life Sci Initiat, Jupiter, FL 33458 USA

关键词: Serotonin;    5-HT2C receptor;    Morphine;    Behavioral sensitization;    Withdrawal;    Ventral tegmental area;    Nucleus accumbens;    Locus coeruleus;   

DOI  :  10.1016/j.neuropharm.2015.09.031

来源: Elsevier

【 摘 要 】

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-HT2C receptor (5-HT2CR) agonists suppress psychostimulant nicotine or cocaine-induced behavioral sensitization and drug-seeking behavior; however, the impact of 5-HT2CR agonists on behaviors relevant to opioid abuse and dependence has not been reported. In the present study, the effects of 5-HT2CR 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-HT2CR 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-HT2CR antagonist, prevented the lorcaserin-mediated suppression of behavioral sensitization and withdrawal. Chronic morphine treatment was associated with an increase in the expression of 5-HT2CR protein in the ventral tegmental area, locus coeruleus and nucleus accumbens. These findings suggest that 5-HT2CR can modulate behavioral sensitization and withdrawal in morphine-dependent mice, and the activation of 5HT(2C)R may represent a new avenue for the treatment of opioid addiction. (C) 2015 Elsevier Ltd. All rights reserved.

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