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.

journal_name

J Neurochem

authors

Shibasaki M,Masukawa D,Ishii K,Yamagishi Y,Mori T,Suzuki T

doi

10.1111/jnc.12258

subject

Has Abstract

pub_date

2013-06-01 00:00:00

pages

747-55

issue

5

eissn

0022-3042

issn

1471-4159

journal_volume

125

pub_type

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