Involvement of the K plus -Cl co-transporter KCC2 in the sensitization to morphine-induced hyperlocomotion under chronic treatment with zolpidem in the mesolimbic system

作者：Shibasaki Masahiro; Masukawa Daiki; Ishii Kazunori; Yamagishi Yui; Mori Tomohisa; Suzuki Tsutomu^*

来源：Journal of Neurochemistry, 2013, 125(5): 747-755.

DOI：10.1111/jnc.12258

• benzodiazepine
• drug dependence
• KCC2
• morphine
• nucleus accumbens
• zolpidem

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 -aminobutyric acid A-type receptor (GABAAR) 1 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 (pPKC). Furthermore, PP-1 directly associated with KCC2 and pPKC, whereas pPKC 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 pPKC-PP-1-KCC2 pathway by chronic treatment with zolpidem.

• 出版日期2013-6