title: The pharmacodynamics of PK 11195 in diazepam-dependent male and female rats.
abstract: These studies were undertaken to 1) determine whether repeated dosing with the peripheral benzodiazepine antagonist PK 11195 alters its ability to precipitate withdrawal abstinence in diazepam-dependent rats; 2) whether the administration of PK 11195 and the central benzodiazepine antagonist, flumazenil, 3 days apart to the same rat produces an ordering effect in the intensity of withdrawal abstinence; 3) whether there are gender differences in these effects. Age-matched male and female Sprague Dawley rats had capsules implanted weekly that contained approximately equal (mg/kg) doses of diazepam (120 and 90 mg, respectively) or empty capsules (controls). After 5 implants, the maximum precipitated withdrawal score (PAS(MAX)) induced by PK 11195 and/or flumazenil (10 mg/kg/IV, respectively) was measured. Repeated administration of PK 11195 (1x/day for 5 days) induced tolerance with regard to the intensity of the PAS(MAX) and with gender-related differences. When PK 11195 was administered weekly (5 weeks), rather than daily, tolerance did not develop in either sex. The PK 11195- and flumazenil-induced PAS(MAX) was not changed by the order in which they were administered. There were gender differences in that females had a higher PAS(MAX) after flumazenil than after PK 11195 and vocalized more after all treatments than males.
authors.affiliation: Department of Anesthesiology, University of Kentucky, Lexington, KY 40536, USA. sjewell@pop.uky.edu
authors.forename: J W
authors.initials: JW
authors.lastname: Sloan
authors.forename: E P
authors.initials: EP
authors.lastname: Wala
authors.forename: X
authors.initials: X
authors.lastname: Jing
authors.forename: J R
authors.initials: JR
authors.lastname: Holtman
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D003975:Diazepam / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000523:psychology; D012727:Sex Characteristics; D013375:Substance Withdrawal Syndrome / Q000523:psychology; D019966:Substance-Related Disorders / Q000523:psychology*
chemical_list: D014151:Anti-Anxiety Agents; D000970:Antineoplastic Agents; D018757:GABA Modulators; D058787:GABA-A Receptor Antagonists; D007546:Isoquinolines; D005442:Flumazenil; D003975:Diazepam; C037850:PK 11195