Limonene Inhibits Methamphetamine-Induced Sensitizations via the Regulation of Dopamine Receptor Supersensitivity
Sun Mi Gu1,†, Sung Yeon Kim2,†, Santosh Lamichhane2, Jin Tae Hong1,* and Jaesuk Yun1,*
1College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju 28160,
2College of Pharmacy, Wonkwang University, Iksan 54538, Republic of Korea
E-mail: jinthong@chungbuk.ac.kr (Hong JT), jyun@chungbuk.ac.kr (Yun J)
Tel: +82-43-261-2813 (Hong JT), +82-43-261-2827 (Yun J)
Fax: +82-43-268-2732 (Hong JT), +82-43-261-2732 (Yun J)
The first two authors contributed equally to this work.
Received: November 4, 2018; Revised: December 24, 2018; Accepted: January 14, 2019; Published online: February 8, 2019.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
Limonene is a cyclic terpene found in citrus essential oils and inhibits methamphetamine- induced locomotor activity. Drug dependence is a severe neuropsychiatric condition that depends in part on changes in neurotransmission and neuroadaptation, induced by exposure to recreational drugs such as morphine and methamphetamine. In this study, we investigated the effects of limonene on the psychological dependence induced by drug abuse. The development of sensitization, dopamine receptor supersensitivity, and conditioned place preferences in rats was measured following administration of limonene (10 or 20 mg/kg) and methamphetamine (1 mg/kg) for 4 days. Limonene inhibits methamphetamine- induced sensitization to locomotor activity. Expression of dopamine receptor supersensitivity induced by apomorphine, a dopamine receptor agonist, was significantly reduced in limonene-pretreated rats. However, there was no significant difference in methamphetamine-induced conditioned place preferences between the limonene and control groups. These results suggest that limonene may ameliorate drug addiction-related behaviors by regulating postsynaptic dopamine receptor supersensitivity.
Keywords: Dopamine receptor supersensitivity, Methamphetamine, Sensitization, Limonene


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