Regulation of clock and clock-controlled genes during morphine reward and reinforcement: Involvement of the period 2 circadian clock

Author:

Custodio Raly James Perez12ORCID,Kim Mikyung3,Sayson Leandro Val2ORCID,Ortiz Darlene Mae2ORCID,Buctot Danilo2ORCID,Lee Hyun Jun2,Cheong Jae Hoon1,Kim Hee Jin2ORCID

Affiliation:

1. School of Pharmacy, Jeonbuk National University, Jeonju-si, Republic of Korea

2. Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, Seoul, Republic of Korea

3. Department of Chemistry & Life Science, Sahmyook University, Seoul, Republic of Korea

Abstract

Background: Morphine abuse is a devastating disorder that affects millions of people worldwide, and literature evidence indicates a relationship between opioid abuse and the circadian clock. Aim: We explored morphine reward and reinforcement using mouse models with Per2 gene modifications (knockout (KO); overexpression (OE)). Methods: Mice were exposed to various behavioral, electroencephalographic, pharmacological, and molecular tests to assess the effects of morphine and identify the underlying mechanisms with a focus on reward and reinforcement and the corresponding involvement of circadian and clock-controlled gene regulation. Results: Per2 deletion enhances morphine-induced analgesia, locomotor sensitization, conditioned place preference (CPP), and self-administration (SA) in mice, whereas its overexpression attenuated these effects. In addition, reduced withdrawal was observed in Per2 KO mice, whereas an augmented withdrawal response was observed in Per2 OE mice. Moreover, naloxone and SCH 23390 blocked morphine CPP in Per2 KO and wild-type (WT) mice. The rewarding (CPP) and reinforcing effects (SA) observed in morphine-conditioned and morphine self-administered Per2 KO and WT mice were accompanied by activated μ-opioid and dopamine D1 receptors and TH in the mesolimbic (VTA/NAcc) system. Furthermore, genetic modifications of Per2 in mice innately altered some clock genes in response to morphine. Conclusion: These findings improve our understanding of the role of Per2 in morphine-induced psychoactive effects. Our data and those obtained in previous studies indicate that targeting Per2 may have applicability in the treatment of substance abuse.

Funder

National Research Foundation Korea

Ministry of Food and Drug Safety Korea

Publisher

SAGE Publications

Subject

Pharmacology (medical),Psychiatry and Mental health,Pharmacology

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3