title: Flumazenil reverses the decrease in the hypnotic activity of pentobarbital by social isolation stress: are endogenous benzodiazepine receptor ligands involved?
abstract: Long-term social isolation stress has been shown to cause a decrease in pentobarbital (PB)-induced sleeping time in mice. In the present study, to clarify whether the GABAA/benzodiazepine (BZD) receptor system is involved in the decrease in the hypnotic activity of PB by social isolation stress, we examined the effects of BZD receptor ligands on the PB-induced sleep in group-housed and socially isolated mice. Moreover, we also tested whether social isolation stress affects the ability of GABA to stimulate 36Cl- uptake or the modulatory effect of diazepam and PB and GABA-induced stimulation of 36Cl- uptake into synaptoneurosomes prepared from mouse brain. Social isolation stress significantly decreased the PB-induced sleeping time in mice. The BZD receptor diazepam (0.1-0.8 mg/kg, i.p.) dose-dependently prolonged PB sleep in group-housed and isolated mice, but the effect was weaker in isolated mice. In contrast, FG7142 (5-10 mg/kg, i.p.), a BZD receptor inverse agonist, shortened the sleep in group-housed but not in isolated mice. Flumazenil (16.5-33 nmol, i.c.v.), a selective BZD receptor antagonist, caused PB sleep in isolated mice to return to the level of group-housed mice, at the dose that antagonized the effects of diazepam and FG7142 on PB sleep in group-housed mice. However, this antagonist alone produced no effect on PB sleep in group-housed mice. Social isolation stress decreased the ability of GABA (0.6-200 microM) to stimulate 36Cl- uptake into synaptoneurosomes but this stress had no effect on PB- and diazepam-induced enhancement of GABA-stimulated 36Cl- uptake. These results suggest that endogenous substance(s) with an inverse BZD receptor agonist-like property and the changes in the ability of GABA to stimulate chloride ion channels are involved in the decrease in the hypnotic activity of pentobarbital following social isolation stress.
authors.affiliation: Department of Pharmacology, Research Institute for Wakan-Yaku (Oriental Medicines), Toyama Medical and Pharmaceutical University, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ojima
authors.forename: K
authors.initials: K
authors.lastname: Matsumoto
authors.forename: H
authors.initials: H
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D002243:Carbolines / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010424:Pentobarbital / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D012890:Sleep / Q000187:drug effects; D012934:Social Isolation / Q000523:psychology*; D013315:Stress, Psychological / Q000523:psychology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D002243:Carbolines; D002712:Chlorides; D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D006993:Hypnotics and Sedatives; D008024:Ligands; D011963:Receptors, GABA-A; D005442:Flumazenil; C035874:FG 7142; D010424:Pentobarbital; D003975:Diazepam