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This study was undertaken to evaluate the effect of acute and repeated (daily and weekly) intravenous (IV) administration of PK 11 195 (PK; 10 mg kg(-1)) on body weight (BW) in Sprague-Dawley male and female rats exposed for 4-8 weeks to diazepam (DZ) slowly released from Silastic capsules (120 and 90 mg/capsule/week for males and females, respectively). Rats implanted with empty capsules served as controls. Both acute and repeated (daily and weekly) administration of PK inhibited BW gain to a greater extent in male than in female rats that received identical treatment. There was no difference in PK effect between DZ-treated and control rats. Furthermore, regardless of treatment or gender, PK-induced inhibition of BW gain lessened during repeated administration of PK. The present data indicate that PK-induced inhibition of BW gain is related to gender rather than to chronic DZ treatment., (Copyright 2000 Academic Press.)

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.

In spite of the extensive use of the peripheral benzodiazepine (BZ) receptor antagonist, PK 11195 (PK), in pharmacological studies, there is a lack of information of its pharmacokinetics in the rat. In this study the pharmacokinetics of PK were determined after bolus intravenous (i.v.) administration in rat. The effects of dose and gender were evaluated in Sprague-Dawley age-matched male and female rats after the injection of PK (5, 10, 20 mg kg(-1)). Plasma was collected at 5-300 min. Levels of PK in plasma and brain were determined by a novel HPLC method. The stability of PK in blood in vitro was determined. PK is stable in rat blood in vitro. The pharmacokinetics of PK are described by a two-compartment model. The half-lives for distribution ( approximately 0.14 h) and elimination ( approximately 5.4 h) are not related to dose. The large volume of distribution (9-24 l kg(-1)) indicates an extensive distribution outside plasma. Total plasma clearance increases with increasing dose (23-42 ml min(-1)kg(-1)). The brain/plasma ratio ( approximately 3) is not related to dose. These finding suggest that the pharmacokinetics of PK are related to dose (5-20 mg kg(-1)) and gender in rat., (Copyright 2000 Academic Press.)

Female rats were exposed to diazepam (DZ) implants (90 mg/week) or to empty capsules (controls) for 5 weeks. Rats were focally injected (1 microl) into the substantia nigra (SNR) with the central (CBR) and peripheral (PBR) benzodiazepine receptor antagonists, flumazenil [(FLU) 6.25, 12.5, or 25 microg], and PK 11195 [(PK) 3.125, 6.25, 12.5, or 25 microg], respectively. Rats were observed for behavioral and EEG manifestation of withdrawal syndrome. In female rats, both FLU and PK induced a dose-related precipitated abstinence score (PAS), tachypnea, and head bobbing. Twitches and jerks tended to increase with increasing dose of both FLU and PK. Furthermore, FLU evoked dose-related turning and head and body tremors. The FLU- and the PK-induced PAS were accompanied by an increase in total power of the EEG in the SNR. The involvement of the CBR and PBR in physical dependence on DZ in the SNR is suggested. The present data in female rats are discussed with regard to similarities and differences with previous studies in male rats.

Six female rats had a loading dose of 180 mg of diazepam (DZ) contained in two Silastic capsules implanted in their backs. Thereafter, a single 90-mg capsule was implanted weekly for 4 weeks prior to weekly microinjections of 1 microl of flumazenil (6.25, 12.5, or 25 microg) and PK 11195 (3.125, 6.25, or 12.5 microg) or vehicle into the CA1. Three control rats had empty capsules implanted but received only the high dose of flumazenil after 5 weeks. The time of DZ exposure spanned 8 weeks. Mean steady-state plasma levels of DZ were 1.06 +/- 0.11, and the mean total (DZ + metabolites) was 2.46 microg/ml +/- 0.37. Flumazenil elicited a dose-related precipitated withdrawal score (PAS) in DZ-treated rats (but not in controls) characterized by dose-related increases in convulsive (twitches and jerks), motor and autonomic signs, dose-related increases in the percent of total power in the low frequency (1-4 Hz), and decreases in the high-frequency (18-26 Hz) bands of the EEG recorded from the dentate and the amygdala. PK 11195 produced a dose-related increase in the 4-12 Hz band of the EEG recorded from the CA1, whereas the PAS was mild and not dose-related. However, the 6.25 and 12.5-microg doses elicited a significant PAS that tended to increase with dose. These data indicate that chronic DZ produces dependence, and that in the CA1 it involves the participation of central and possibly peripheral benzodiazepine (BZ) receptors located within this structure.

The abilities of the central (CBR) and the peripheral (PBR) benzodiazepine receptor antagonists, flumazenil (FLU) and PK 11195 (PK), to precipitate an abstinence syndrome in diazepam (DZ)-dependent rats have been evaluated. Female rats were exposed for 5 weeks to DZ slowly released from SC implanted silastic capsules (90 mg/capsule per week) and thereafter they were challenged in weekly intervals with IV injections of FLU (10, 20, 40 mg/kg) or PK (5, 10, 20 mg/kg), respectively. The maximum abstinence scores tended to increase with the dose of FLU but not with the dose of PK. Although FLU and PK precipitated some common abstinence signs, there were marked differences between these antagonists. FLU evoked dose-related tonic-clonic and clonic convulsions (five out of six rats), whereas PK (10 mg/kg) induced convulsions in only one rat (out of five); tachypnea tended to increase with the dose of both FLU and PK; twitches and jerks, backing and writhing had a significant regression on the dose of FLU; rearing tended to decrease with the dose of PK whereas FLU-evoked head bobbing and PK-evoked twitches and jerks had inverse U-shaped dose-response curves. In comparison to FLU, similar doses of PK (10 and 20 mg/kg) induced a lower precipitated abstinence score (P < 0.05) and a less intense tachypnea (P < 0.05). The data indicate that the chronic continuous exposure to DZ (and/or its active metabolites) affects both CBR and PBR in the rat; however, the abstinence syndromes produced by the CBR and PBR antagonists, FLU and PK, differ in overall intensities and in the diversity of evoked abstinence signs.

The central and peripheral benzodiazepine (BZ) receptor antagonists, flumazenil (FLU) and PK 11195 (PK), administered intrathecally (IT) to diazepam (DZ)-dependent rats produced a precipitated abstinence syndrome. The scores for abstinence increased with increasing dose of FLU but not with increasing dose of PK. Twitches and jerks increased with increased doses of both. Head and body tremors were produced by FLU, but not by PK. Neither FLU nor PK precipitated abstinence in controls. In DZ-dependent rats IT administered FLU and PK did not significantly change the spectral content and the total power of the EEG. The data indicate that an abstinence syndrome is precipitated at the spinal level in DZ-dependent rats and that both central and peripheral BZ receptors are involved.