Subsensitivity to mitochondrial diazepam binding inhibitor receptor agonist FGIN-1-27-induced antiseizure effect in diazepam-withdrawn mice.

Abstract

We investigated the role of the mitochondrial diazepam binding inhibitor receptor (MDR) in diazepam-withdrawal seizure. In chronically vehicle-treated mice, the potent and selective MDR agonist FGIN-1-27 (N,N-di-n-hexyl 2-(4-fluorophenyl)indole-3-acetamide: 30 microg/mouse, i.c.v.) markedly increased the threshold for pentylenetetrazole (PTZ)-induced seizure. The antiseizure effect of FGIN-1-27 was blocked by pretreatment with the selective MDR antagonist PK11195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxa mide). In chronically diazepam-treated mice, the seizure threshold of PTZ was decreased during diazepam withdrawal, indicating withdrawal hyperexcitability. Interestingly, FGIN-1-27 (30 microg/mouse, i.c.v.) failed to increase the seizure threshold of PTZ in diazepam-withdrawn mice, in contrast to its effect in chronically vehicle-treated mice. These findings suggest that the sensitivity of MDR-mediated pathways in the brain may be decreased during diazepam withdrawal.

• Authors: M Tsuda, T Suzuki, M Misawa
• Journal: Life sciences (Life Sci) Vol. 62 Issue 14 Pg. PL213-7 ( 1998) ISSN: 0024-3205 [Print] Netherlands
• PMID: 9570345 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticonvulsants
• Indoleacetic Acids
• Receptors, Cytoplasmic and Nuclear
• diazepam-binding inhibitor receptor
• N,N-di-n-hexyl-2-(4-fluorophenyl)indole-3-acetamide
• Diazepam

Topics

• Animals
• Anticonvulsants (adverse effects)
• Diazepam (adverse effects)
• Indoleacetic Acids (pharmacology)
• Injections, Intraventricular
• Male
• Mice
• Mitochondria (drug effects, metabolism)
• Receptors, Cytoplasmic and Nuclear (agonists)
• Substance Withdrawal Syndrome