Involvement of the “peripheral” benzodiazepine receptor type (ω3) in the tolerance to the electroencephalographic effects of benzodiazepines in rats: Comparison of diazepam and clonazepam

doi:10.1016/0091-3057(90)90381-Q

Pharmacology Biochemistry and Behavior

Volume 35, Issue 4, April 1990, Pages 933-936

https://doi.org/10.1016/0091-3057(90)90381-Q Get rights and content

Abstract

Rapid tolerance to the sedative effect of large doses of diazepam (10 mg/kg IV), but not of large doses of clonazepam (2 mg/kg IV) occurs in rats after 5 days of treatment on a once-a-day regimen. Electroencephalographic (EEG) studies show that such behavioral tolerance is associated with a decreased induction of spindle bursts and with an increased induction of 20–30 Hz waves (β-like activity). Administration of clonazepam plus the agonist of the “peripheral” benzodiazepine receptor type (ω₃) Ro 5-4864 (4 mg/kg IV) for 5 days induces signs of behavioral and EEG tolerance to sedative effects of the benzodiazepine agonist. In animals treated for 5 days with diazepam plus the ω₃ antagonist PK 11195 (5 mg/kg IV), no signs of EEG and behavioral tolerance are observed. These results suggest that ω₃ type activation influences the development of rapid tolerance to the sedative effect of diazepam in rats.

References (27)

J. Benavides et al.
Opposite effects of an agonist, Ro 5-4864, and an antagonist, PK 11195, of the peripheral type benzodiazepine binding sites on audiogenic seizures in DBA/2J mice
Life Sci.
(1984)
S. File
Tolerance to the behavioral actions of benzodiazepines
Neurosci. Biobehav. Rev.
(1985)
J.P. Gent et al.
Differences between the tolerance characteristics of two anticonvulsant benzodiazepines
Life Sci.
(1985)
S.Z. Langer et al.
Imidazopyridines as a tool for the characterization of benzodiazepine receptors: a proposal for a pharmacological classification as omega receptor subtypes
Pharmacol. Biochem. Behav.
(1988)
V.G. Longo et al.
Modifications of brain electrical activity after activation of the benzodiazepine receptor types in rats and rabbits
Pharmacol. Biochem. Behav.
(1988)
M. Massotti
Electroencephalographic investigation in rabbits of drugs acting at GABA-benzodiazepine-barbiturate/picrotoxin receptor complex
Pharmacol. Biochem. Behav.
(1985)
L. Mele et al.
Chronic administration of diazepam to rats causes changes in EEG patterns and in coupling between GABA receptors and benzodiazepine binding sites in vitro
Brain Res.
(1984)
S. Pellow et al.
Characteristics of an atypical benzodiazepine, Ro 5-4864
Neurosci. Biobehav. Rev.
(1984)
S. Pellow
Can drugs effects on anxiety and convulsions be separated?
Neurosci. Biobehav. Rev.
(1985)
R. Ramanjaneyulu et al.
Interaction between pentamethylenetetrazol and tetrazole analogues with the picrotoxin site of benzodiazepine-GABA receptor-ionophore
Eur. J. Pharmacol.
(1984)

W. Schallek et al.

Effects of benzodiazepines on spontaneous EEG and arousal responses of cats

E. Schwarz et al.

Changes in EEG, blood levels, mood scales and performance scored during long term treatment with diazepam, phenobarbital or placebo in patients

Prog. Neuropsychopharmacol.

(1982)

A. Valerio et al.

Electroencephalographic changes after short-term exposure to agonists of benzodiazepine receptors in the rat

Pharmacol. Biochem. Behav.

(1988)

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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 bloodin 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 (≈0.14 h) and elimination (≈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⁻¹kg⁻¹). The brain/plasma ratio (≈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.
The effect of PK 11 195, a specific antagonist of the peripheral benzodiazepine receptors, on body weight in rats chronically exposed to diazepam
2000, Pharmacological Research
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.
Precipitated withdrawal in the substantia nigra in diazepam-dependent female rats
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Female rats were exposed to diazepam (DZ) implants (90 mg/week) or to empty capsules (controls) for 5 weeks. Rats were focally injected (1 μl) into the substantia nigra (SNR) with the central (CBR) and peripheral (PBR) benzodiazepine receptor antagonists, flumazenil [(FLU} 6.25, 12.5,or 25 μg], and PK 11195 [(PK) 3.125, 6.25, 12.5, or 25 μg], 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.
Substantia nigra: The involvement of central and peripheral benzodiazepine receptors in physical dependence on diazepam as evidenced by behavioral and EEG effects
1999, Pharmacology Biochemistry and Behavior
Male rats chronically exposed to diazepam (DZ) slowly released from subcutaneously implanted silastic capsules along with empty capsule control rats were focally injected (1 μl) into the substantia nigra (SNR) with the central (CBR) and peripheral (PBR) benzodiazepine receptor antagonists, flumazenil [(FLU) 6.25, 12.5, 25 μg] and PK 11195 [(PK) 3.125, 6.25, 12.5, 25 μg], respectively (weekly intervals; Latin square design). Rats were observed for signs of withdrawal and the EEG was recorded simultaneously from the site of injection (SNR), caudate putamen, thalamus, hippocampus, and frontal cortex. In DZ-dependent rats the Precipitated Abstinence Score (PAS) was significantly related to dose of FLU. The PAS increased with increasing doses of PK (3.125–12.5 μg); however, the highest dose of PK (25 μg) showed less effect. The rapid onset of the PAS was accompanied by a rise in the total power (1–32 Hz) of the EEG (TP_EEG) in the SNR and other brain areas. The PAS and TP_EEG had similar time courses. Intranigrally injected FLU and PK did not evoke clonic and tonic–clonic convulsions; however, both antagonists induced dose-related twitches and jerks. Additionally, FLU precipitated a dose-related tachypnea and increases in turning and backing. Chronic DZ treatment altered the spectral content of the EEG, as indicated by a decrease and an increase of the slow and fast frequency bands, respectively. FLU and PK rapidly but transiently reversed the EEG. Data suggest that in the SNR the CBR mediate autonomic and motor signs of DZ withdrawal, while both the CBR and PBR are responsible for twitches and jerks and alteration of the EEG. It is possible that PK also acts on the site linked to a GABA_A/CBR/ionophore.
Diazepam-treated female rats: Flumazenil- and PK 11195-induced withdrawal in the hippocampus CA1
1998, Pharmacology Biochemistry and Behavior
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 μl of flumazenil (6.25, 12.5, or 25 μg) and PK 11195 (3.125, 6.25, or 12.5 μg) 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 μg/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-μg 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.
Peripheral-type benzodiazepine receptor ligands and serum steroid hormones
1997, Brain Research
The peripheral-type benzodiazepine receptors (PBR) are involved in various cellular functions, including steroidogenesis. The impact of these receptor ligands has been demonstrated mainly in steroidogenic cells. The aim of the present study was to assess in intact female rats the effect of chronic (21 days) administration of the PBR ligands PK 11195 (15 mg/kg) and Ro 5-4864 (5 mg/kg), the mixed ligand diazepam (5 mg/kg), and the central benzodiazepine receptor ligand clonazepam (1 mg/kg) on PBR binding characteristics in steroidogenic (ovary and adrenal) and non-steroidogenic (uterus and kidney) organs, as well as on serum hormonal steroids (estradiol, progesterone, and corticosterone). Selective and mixed PBR ligands up-regulated PBR density in the two steroidogenic organs, while Ro 5-4864 also induced elevation of the receptor density in the non-steroidogenic organs. In contrast to Ro 5-4864, PK 11195 treatment down-regulated renal PBR. Clonazepam elevated adrenal PBR. On the serum hormonal level, Ro 5-4864 suppressed estradiol secretion. The other ligands did not affect hormonal steroid levels. It appears that in female rats, at least at these doses and dosing schedules, there is no correlation between the impact of chronic in vivo exposure to these agents on PBR density and ovarian and adrenal hormone levels.

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Involvement of the “peripheral” benzodiazepine receptor type (ω3) in the tolerance to the electroencephalographic effects of benzodiazepines in rats: Comparison of diazepam and clonazepam

Abstract

Life Sci.

Neurosci. Biobehav. Rev.

Life Sci.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Brain Res.

Neurosci. Biobehav. Rev.

Neurosci. Biobehav. Rev.

Eur. J. Pharmacol.

Prog. Neuropsychopharmacol.

Pharmacol. Biochem. Behav.

Involvement of the “peripheral” benzodiazepine receptor type (ω₃) in the tolerance to the electroencephalographic effects of benzodiazepines in rats: Comparison of diazepam and clonazepam