title: Blockade of Serotonin 5-HT2AReceptors Suppresses Behavioral Sensitization and Naloxone-Precipitated Withdrawal Symptoms in Morphine-Treated Mice.
abstract: The increasing prescription of opioids is fueling an epidemic of addiction and overdose deaths. Morphine is a highly addictive drug characterized by a high relapse rate - even after a long period of abstinence. Serotonin (5-HT) neurotransmission participates in the development of morphine dependence, as well as the expression of morphine withdrawal. In this study, we examined the effect of blockade of 5-HT2Areceptors (5-HT2ARs) on morphine-induced behavioral sensitization and withdrawal in male mice. 5-HT2AR antagonist MDL 11,939 (0.5 mg/kg, i.p.) suppressed acute morphine (5.0 mg/kg, s.c.)-induced increase in locomotor activity. Mice received morphine (10 mg/kg, s.c.) twice a day for 3 days and then drug treatment was suspended for 5 days. On day 9, a challenge dose of morphine (10 mg/kg) was administered to induce the expression of behavioral sensitization. MDL 11,939 (0.5 mg/kg, i.p.) pretreatment suppressed the expression of morphine-induced behavioral sensitization. Another cohort of mice received increasing doses of morphine over a 7-day period to induce morphine-dependence. MDL 11,939 (0.5 mg/kg, i.p.) prevented naloxone-precipitated withdrawal in morphine-dependent mice on day 7. Moreover, chronic morphine treatment increased 5-HT2AR protein level and decreased the phosphorylation of extracellular signal-regulated kinases in the prefrontal cortex. Together, these results by the first time demonstrate that 5-HT2ARs modulate opioid dependence and blockade of 5-HT2AR may represent a novel strategy for the treatment of morphine use disorders.
  
  
  CONCLUSIONS
  (i)Blockade of 5-HT2Areceptors suppresses the expression of morphine-induced behavioral sensitization.(ii)Blockade of 5-HT2Areceptors suppresses naloxone-precipitated withdrawal in morphine-treated mice.(iii)Chronic morphine exposure induces an increase in 5-HT2Areceptor protein level and a decrease in ERK protein phosphorylation in prefrontal cortex.
authors.affiliation: College of Basic Medical Sciences, Anhui Medical University Hefei, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Pang
authors.affiliation: College of Basic Medical Sciences, Anhui Medical University Hefei, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Wu
authors.affiliation: College of Medicine, Anhui University of Science and Technology Huainan, China.
authors.forename: Xinrong
authors.initials: X
authors.lastname: Tao
authors.affiliation: College of Medicine, Anhui University of Science and Technology Huainan, China.
authors.forename: Ruoying
authors.initials: R
authors.lastname: Mao
authors.affiliation: College of Medicine, Anhui University of Science and Technology Huainan, China.
authors.forename: Xueke
authors.initials: X
authors.lastname: Liu
authors.affiliation: Jiangsu Province Key Laboratory of Anesthesiology, College of Anesthesiology, Xuzhou Medical University Xuzhou, China.
authors.forename: Yong-Mei
authors.initials: YM
authors.lastname: Zhang
authors.affiliation: College of Basic Medical Sciences, Anhui Medical University Hefei, China.
authors.forename: Guangwu
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Psychology, Jupiter Life Science Initiative, Florida Atlantic University, Jupiter FL, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Stackman
authors.affiliation: College of Basic Medical Sciences, Anhui Medical University Hefei, China.
authors.forename: Liuyi
authors.initials: L
authors.lastname: Dong
authors.affiliation: College of Basic Medical Sciences, Anhui Medical UniversityHefei, China; Department of Psychology, Jupiter Life Science Initiative, Florida Atlantic University, JupiterFL, USA.
authors.forename: Gongliang
authors.initials: G
authors.lastname: Zhang
keywords: 5-HT2A receptor; behavioral sensitization; hippocampus; morphine; prefrontal cortex; serotonin; withdrawal