Jpn. J. Pharmacol. 81 (1), 1 - 6 (1999)

-Current Perspective-
Contribution of Glutamate Receptors to Benzodiazepins Withdrawal Signs

Makoto Tsuda¹, Norifumi Shimizu² and Tsutomu Suzuki^3,*

¹Section of Neuropharmacology, Division of Pharmacology, National Institute of Health Sciences, 1 - 18 - 1 Kamiyoga, Setagaya-ku, Tokyo 158 - 8501, Japan
²Department of Pharmacology, Wakayama Medical College, 811 - 1 Kimiidera, Wakayama-city, Wakayama 641 - 0012, Japan
³Department of Toxicology, School of Pharmacy, Hoshi University, 2 - 4 - 41 Ebara, Shinagawa-ku, Tokyo 142 - 8501, Japan
* To whom correspondence should be addressed.

Abstract: Recent research has demonstrated that the receptor for glutamate, a major excitatory neurotransmitter, may play an important role in the expression of benzodiazepine withdrawal signs. This proposal is based on various observations. For example, antagonists for N-methyl-d-aspartate (NMDA), non-NMDA and metabotropic glutamate (mGlu) receptors can suppress the behavioral signs of benzodiazepine withdrawal in mice and rats. Furthermore, the NMDA receptor in the cerebrocortical area of diazepam-withdrawn rats is upregulated. Finally, the stimulation of phosphoinositide hydrolysis mediated by mGluR is enhanced in cerebrocortical slices from lorazepam-withdrawn mice. These findings show that the upregulation of signal transduction mediated by glutamate receptors during diazepam withdrawal plays a role in the neuroadaptive response responsible for the expression of diazepam withdrawal signs. Furthermore, ligands for glutamate receptors may be suitable targets for treating benzodiazepine withdrawal signs.

Keywords: Benzodiazepine, Withdrawal sign, Glutamate receptor