Reduction of group II metabotropic glutamate receptors during development of benzodiazepine dependence

Ritsuko Okamoto, Yoshinori Itoh, Yusuke Murata, Daisuke Kobayashi, Masako Hosoi, Kazunori Mine

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Prolonged use of benzodiazepines often leads to dependence and withdrawal syndrome. However, the cellular mechanisms underlying benzodiazepine dependence have not been fully clarified. Several investigators have shown an involvement of metabotropic glutamate receptors (mGluRs) in the pathophysiology of dependence or withdrawal. This study was performed to elucidate the role of mGluRs in benzodiazepine dependence. Withdrawal signs were precipitated in mice by flumazenil injection (25 mg/kg) after continuous subcutaneous infusion of benzodiazepines for 7 days, and the effects of several Gi-coupled receptor ligands on forskolin-stimulated cyclic AMP accumulation were examined in the cerebral cortex of mice. The mRNA expression for mGluRs was determined by RT-PCR. A single injection of flumazenil precipitated typical withdrawal signs such as tail elevation and tremor in mice treated with diazepam or alprazolam, but not quazepam. The inhibitory effect of nonselective mGluR ligands on adenylate cyclase activity was diminished in mice that showed signs of benzodiazepine withdrawal. The mRNA expression levels of mGluR2 and mGluR3 were lowered in the cerebral cortex of mice pretreated with diazepam or alprazolam. Our findings suggest that the reduction in the expression of group II mGluRs subunits may be involved in the development of benzodiazepine dependence.

Original languageEnglish
Pages (from-to)145-152
Number of pages8
JournalPharmacology
Volume91
Issue number3-4
DOIs
Publication statusPublished - May 1 2013

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All Science Journal Classification (ASJC) codes

  • Pharmacology

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