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Front Pharmacol. 2016 Dec 26;7:514. doi: 10.3389/fphar.2016.00514. eCollection 2016.

Blockade of Serotonin 5-HT2A Receptors Suppresses Behavioral Sensitization and Naloxone-Precipitated Withdrawal Symptoms in Morphine-Treated Mice.

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College of Basic Medical Sciences, Anhui Medical University Hefei, China.
College of Medicine, Anhui University of Science and Technology Huainan, China.
Jiangsu Province Key Laboratory of Anesthesiology, College of Anesthesiology, Xuzhou Medical University Xuzhou, China.
Department of Psychology, Jupiter Life Science Initiative, Florida Atlantic University, Jupiter FL, USA.
College of Basic Medical Sciences, Anhui Medical UniversityHefei, China; Department of Psychology, Jupiter Life Science Initiative, Florida Atlantic University, JupiterFL, USA.


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-HT2A receptors (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.


(i)Blockade of 5-HT2A receptors suppresses the expression of morphine-induced behavioral sensitization.(ii)Blockade of 5-HT2A receptors suppresses naloxone-precipitated withdrawal in morphine-treated mice.(iii)Chronic morphine exposure induces an increase in 5-HT2A receptor protein level and a decrease in ERK protein phosphorylation in prefrontal cortex.


5-HT2A receptor; behavioral sensitization; hippocampus; morphine; prefrontal cortex; serotonin; withdrawal

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