Subsensitivity to mitochondrial diazepam binding inhibitor receptor agonist FGIN-1-27-induced antiseizure effect in diazepam-withdrawn mice.
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 Interestingly, FGIN-1-27 (30 microg/mouse, i.c.v.) failed to increase the seizure threshold of PTZ in diazepam-withdrawn mice, in contrast to its effect in chronically vehicle-treated mice.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.
Tsuda
M
M
Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo, Japan.
Suzuki
T
T
Misawa
M
M
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects*; D003975:Diazepam / Q000009:adverse effects*; D007210:Indoleacetic Acids / Q000494:pharmacology*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013375:Substance Withdrawal Syndrome
D000927:Anticonvulsants; D007210:Indoleacetic Acids; D018160:Receptors, Cytoplasmic and Nuclear; C078199:diazepam-binding inhibitor receptor; C081306:N,N-di-n-hexyl-2-(4-fluorophenyl)indole-3-acetamide; D003975:Diazepam