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

Gang Pang; Xian Wu; Xinrong Tao; Ruoying Mao; Xueke Liu; Yong-Mei Zhang; Guangwu Li; Robert W Stackman Jr; Liuyi Dong; Gongliang Zhang

doi:10.3389/fphar.2016.00514

Blockade of Serotonin 5-HT_2A Receptors Suppresses Behavioral Sensitization and Naloxone-Precipitated Withdrawal Symptoms in Morphine-Treated Mice

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

Authors

Affiliations

¹ College of Basic Medical Sciences, Anhui Medical University Hefei, China.
² College of Medicine, Anhui University of Science and Technology Huainan, China.
³ Jiangsu Province Key Laboratory of Anesthesiology, College of Anesthesiology, Xuzhou Medical University Xuzhou, China.
⁴ Department of Psychology, Jupiter Life Science Initiative, Florida Atlantic University, Jupiter FL, USA.
⁵ College of Basic Medical Sciences, Anhui Medical UniversityHefei, China; Department of Psychology, Jupiter Life Science Initiative, Florida Atlantic University, JupiterFL, USA.

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-HT_2A receptors (5-HT_2ARs) on morphine-induced behavioral sensitization and withdrawal in male mice. 5-HT_2AR 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-HT_2AR 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-HT_2ARs modulate opioid dependence and blockade of 5-HT_2AR may represent a novel strategy for the treatment of morphine use disorders.

Highlights: (i)Blockade of 5-HT_2A receptors suppresses the expression of morphine-induced behavioral sensitization.(ii)Blockade of 5-HT_2A receptors suppresses naloxone-precipitated withdrawal in morphine-treated mice.(iii)Chronic morphine exposure induces an increase in 5-HT_2A receptor protein level and a decrease in ERK protein phosphorylation in prefrontal cortex.

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

Grants and funding

R01 MH086591/MH/NIMH NIH HHS/United States