Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2020.041
MeBib Suppressed Methamphetamine Self-Administration Response via Inhibition of BDNF/ERK/CREB Signal Pathway in the Hippocampus
Buyun Kim1,†, Sonam Jha1,†, Ji Hae Seo2, Chul-Ho Jeong1, Sooyeun Lee1, Sangkil Lee1, Young Ho Seo1,* and
Byoungduck Park1,*
1College of Pharmacy, Keimyung University, Daegu 42601,
2Department of Biochemistry, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea
E-mail: bdpark@kmu.ac.kr (Park B), seoyho@kmu.ac.kr (Seo YH)
Tel: +82-53-580-6653 (Park B), +82-53-580-6639 (Seo YH)
Fax: +82-53-580-6645 (Park B), +82-53-580-6645 (Seo YH)
†The first two authors contributed equally to this work.
Received: March 19, 2020; Revised: April 23, 2020; Accepted: May 9, 2020; Published online: May 29, 2020.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Methamphetamine (MA) is one of the most commonly abused drugs in the world by illegal drug users. Addiction to MA is a serious public health problem and effective therapies do not exist to date. It has also been reported that behavior induced by psychostimulants such as MA is related to histone deacetylase (HDAC). MeBib is an HDAC6 inhibitor derived from a benzimidazole scaffold. Many benzimidazole-containing compounds exhibit a wide range of pharmacological activity. In this study, we investigated whether HDAC6 inhibitor MeBib modulates the behavioral response in MA self-administered rats. Our results demonstrated that the number of active lever presses in MA self-administered rats was reduced by pretreatment with MeBib. In the hippocampus of rats, we also found MA administration promotes GluN2B, an NMDA receptor subunit, expression, which results in sequential activation of ERK/CREB/BDNF pathway, however, MeBib abrogated it. Collectively, we suggest that MeBib prevents the MA seeking response induced by MA administration and therefore, represents a potent candidate as an MA addiction inhibitor.
Keywords: Methamphetamine, Self-administration, MeBib, HDAC6 inhibitor, Hippocampus


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