title: Methamphetamine induces endoplasmic reticulum stress related gene CHOP/Gadd153/ddit3 in dopaminergic cells.
abstract: We examined the toxicity of methamphetamine and dopamine in CATH.a cells, which were derived from mouse dopamine-producing neural cells in the central nervous system. Use of the quantitative real-time polymerase chain reaction revealed that transcripts of the endoplasmic reticulum stress related gene (CHOP/Gadd153/ddit3) were considerably induced at 24-48 h after methamphetamine administration (but only under apoptotic conditions), whereas dopamine slightly induced CHOP/Gadd153/ddit3 transcripts at an early stage. We also found that dopamine and methamphetamine weakly induced transcripts for the glucose-regulated protein 78 gene (Grp78/Bip) at the early stage. Analysis by immunofluorescence microscopy demonstrated an increase of　CHOP/Gadd153/ddit3 and Grp78/Bip proteins at 24 h after methamphetamine administration. Treatment of CATH.a cells with methamphetamine caused a re-distribution of dopamine inside the cells, which mimicked the presynaptic activity of neurons with cell bodies located in the ventral tegmental area or the substantia nigra. Thus, we have demonstrated the existence of endoplasmic reticulum stress in a model of presynaptic dopaminergic neurons for the first time. Together with the recent evidence suggesting the importance of presynaptic toxicity, our findings provide new insights into the mechanisms of dopamine toxicity, which might represent one of the most important mechanisms of methamphetamine toxicity and addiction.
authors.affiliation: Department of Pharmacology, Iwate Medical School, Uchimaru, Morioka, Japan. yirie@iwate-med.ac.jp
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Irie
authors.forename: Makio
authors.initials: M
authors.lastname: Saeki
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tanaka
authors.forename: Yonehiro
authors.initials: Y
authors.lastname: Kanemura
authors.forename: Shinpei
authors.initials: S
authors.lastname: Otake
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ozono
authors.forename: Toshisaburou
authors.initials: T
authors.lastname: Nagai
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kondo
authors.forename: Kenzo
authors.initials: K
authors.lastname: Kudo
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kamisaki
authors.forename: Naomasa
authors.initials: N
authors.lastname: Miki
authors.forename: Eiichi
authors.initials: E
authors.lastname: Taira
mesh_terms: D000818:Animals; D004298:Dopamine / Q000096:biosynthesis; D015259:Dopamine Agents / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005786:Gene Expression Regulation / Q000187:drug effects; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C497250:Ddit3 protein, mouse; D015259:Dopamine Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D017447:Receptors, Dopamine D1; D051742:Transcription Factor CHOP; D008694:Methamphetamine; D004298:Dopamine