title: Involvement of the K+-Cl- co-transporter KCC2 in the sensitization to morphine-induced hyperlocomotion under chronic treatment with zolpidem in the mesolimbic system.
abstract: Benzodiazepines are commonly used as sedatives, sleeping aids, and anti-anxiety drugs. However, chronic treatment with benzodiazepines is known to induce dependence, which is considered related to neuroplastic changes in the mesolimbic system. This study investigated the involvement of K(+) -Cl(-) co-transporter 2 (KCC2) in the sensitization to morphine-induced hyperlocomotion after chronic treatment with zolpidem [a selective agonist of γ-aminobutyric acid A-type receptor (GABAA R) α1 subunit]. In this study, chronic treatment with zolpidem enhanced morphine-induced hyperlocomotion, which is accompanied by the up-regulation of KCC2 in the limbic forebrain. We also found that chronic treatment with zolpidem induced the down-regulation of protein phosphatase-1 (PP-1) as well as the up-regulation of phosphorylated protein kinase C γ (pPKCγ). Furthermore, PP-1 directly associated with KCC2 and pPKCγ, whereas pPKCγ did not associate with KCC2. On the other hand, pre-treatment with furosemide (a KCC2 inhibitor) suppressed the enhancing effects of zolpidem on morphine-induced hyperlocomotion. These results suggest that the mesolimbic dopaminergic system could be amenable to neuroplastic change through a pPKCγ-PP-1-KCC2 pathway by chronic treatment with zolpidem.
authors.affiliation: Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo 142-8501, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shibasaki
authors.forename: Daiki
authors.initials: D
authors.lastname: Masukawa
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ishii
authors.forename: Yui
authors.initials: Y
authors.lastname: Yamagishi
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Mori
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D004357:Drug Synergism; D008032:Limbic System / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000008:administration & dosage*; D011595:Psychomotor Agitation / Q000378:metabolism*; D011725:Pyridines / Q000008:administration & dosage*; D027981:Symporters / Q000096:biosynthesis / Q000502:physiology*; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D000077334:Zolpidem; D000096922:K Cl- Cotransporters
chemical_list: D009020:Morphine; D011725:Pyridines; D027981:Symporters; D000077334:Zolpidem; D000096922:K Cl- Cotransporters