title: Reduction of group II metabotropic glutamate receptors during development of benzodiazepine dependence.
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.
authors: Department of Psychosomatic Medicine, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.
authors: Ritsuko
authors: R
authors: Okamoto
authors: Yoshinori
authors: Y
authors: Itoh
authors: Yusuke
authors: Y
authors: Murata
authors: Daisuke
authors: D
authors: Kobayashi
authors: Masako
authors: M
authors: Hosoi
authors: Kazunori
authors: K
authors: Mine
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D006719:Homovanillic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics*; D012701:Serotonin / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000503:physiopathology; D019966:Substance-Related Disorders / Q000378:metabolism* / Q000503:physiopathology; D014202:Tremor / Q000139:chemically induced
chemical_list: D018757:GABA Modulators; D018094:Receptors, Metabotropic Glutamate; D015102:3,4-Dihydroxyphenylacetic Acid; D001569:Benzodiazepines; D012701:Serotonin; D005442:Flumazenil; D006897:Hydroxyindoleacetic Acid; D004298:Dopamine; D006719:Homovanillic Acid