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論文
タイトル
タイトル(英)
Overexpression of tyrosine hydroxylase in dopaminergic neurons increased sensitivity to methamphetamine.
参照URL
https://researchmap.jp/ymoriya/published_papers/41329284
著者
著者(英)
Yuka Nago-Iwashita,Yuki Moriya,Satoshi Hara,Ryohei Ogawa,Rina Aida,Katsuya Miyajima,Takenobu Shimura,Shin-Ichi Muramatsu,Soichiro Ide,Kazutaka Ikeda,Hiroshi Ichinose
担当区分
概要
概要(英)
Drug abuse is one of the great social problems in the world and a major healthcare challenge. It is supposed that sensitivity and reactivity to abuse drugs may vary from person to person, while its molecular basis is largely unknown. Dopaminergic neurons are deeply involved in addiction, and tyrosine hydroxylase (TH) catalyzes the first and rate-limiting step of the biosynthesis of dopamine (DA). We investigated the effects of increased TH expression on the metabolism of DA and reactivity to methamphetamine (METH), a drug of abuse, in mice. Wild-type TH (WT-TH) or the S40E mutant of TH (S40E-TH), which is an active form of TH mimicking phosphorylated TH at the 40th serine, was expressed in midbrain dopaminergic neurons using an adeno-associated virus (AAV) vector. The biochemical analysis showed that the turnover rates of DA in the nerve terminals were increased by the expression of WT-TH and S40E-TH, while there were few changes in the DA contents. Next, we administered METH to TH-overexpressing mice. We found that the S40E-TH-expressing mice responded to lower doses of METH than the control mice and WT-TH mice. The stereotyped behaviors appeared first in S40E-TH mice and then in WT-TH and control mice in this order. These data showed that the TH activity and expression level differentially affect DA metabolism in the nerve terminals from that in the cell bodies and that the TH activity and expression level are one of the determining factors for sensitivity and reactivity to METH. We suggest that TH may be a drug target for ameliorating sensitivity to drugs of abuse.
出版者・発行元
出版者・発行元(英)
誌名
誌名(英)
Neurochemistry international
164
開始ページ
105491
終了ページ
105491
出版年月
2023年1月25日
査読の有無
招待の有無
掲載種別
研究論文(学術雑誌)
ISSN
DOI URL
https://doi.org/10.1016/j.neuint.2023.105491
共同研究・競争的資金等の研究課題
研究者
池田 和隆 (イケダ カズタカ) , 井手 聡一郎 (イデ ソウイチロウ) , 森屋 由紀 (モリヤ ユキ)