S. B. Seredenin

Hereditary Traits of Animals with Different Types of Reaction to Stress and Benzodiazepine Tranquilizers

Individual reactions to benzodiazepines have been widely discussed in the literature since these tranquilizers were first accepted into clinical practice (Aleksandrovsky, 1973, 1976). Neither pharmacokinetics nor other pharmacological approaches already clinically approved for other groups of medicaments have provided a reliable means of predicting their effects to date (Dasberg, 1974; Ghoneim et al., 1981). This state of affairs appears to be due to benzodiazepines’ broad pharmacological profile, hampering attempts to account for their varying effects. Further research is obviously required to improve our understanding of them.

Kinetics of [14C]phenazepam excretion in albino rats after single and repeated injections of the drug

During the 5 days after intraperitoneal injection of [14C] phenazepam into albino rats, both intact animals and animals previously receiving phenazepam injections for 15 days, about 77% of the total radioactivity was excreted with the urine and feces. The excretion processes can be described by a first-order equation. The rate of total excretion of phenazepam was identical after single or repeated injections of the drug. Meanwhile, after a single injection of phenazepam into the animals, it was excreted mainly with the urine, whereas after repeated injections it was excreted mainly with the feces. The process of excretion of phenazepam with the urine after repeated injection is biexponential in character.

Ionic regulation of specific3H-diazepam binding depending on emotional stress reaction phenotype

Previous investigations conducted on inbred C57BL/6 (B6) and Balb/C (BC) mice, differing in their reactions to emotional stress in the open field (OF) test showed that these animals are characterized by a whole range or neurochemical differences, which are clearly manifested during development of the stress response [3-5]. The most important fact is that under OF conditions they may react in different ways to benzodiazepine tranquilizers [7]. In an attempt to elucidate the primary mechanism of formation of differences in the reaction to emotional stress and effects of benzodiazepine, we studied the characteristics of endogenous regulation of specific binding of 3H-diazepam and found that the models used differ with respect to dependence of the stimulation action of NaC1 on receptor activity of the benzodiazepine site of the GABA-benzodiazepine receptor complex on concentration [1, 2]. The aim of this investigation was to study ionic regulation of 3H-diazepam reception in the brain of B6 and BC mice against the background of emotional stress in the OF test, and of preliminary injection of benzodiazepine tranquilizers.

Ionic regulation of reception of35S-tert-butylbicyclo-phosphorothionate by brain membranes of inbred mice differing in emotional stress response

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Interaction between GABA- and Cl−-ionophore binding sites of the GABA-benzodiazepine receptor complex in the inbred mouse brain

Previous investigations of the central mechanisms of formation of inherited differences in responses to emotional stress and to benzodiazepine tranquilizers in experiments on C57BL/6 (B6) and BALB/c (C) mice have led to the discovery and description of the phenotypic variants of regulation of the benzodiazepine receptor complex by C1ions [1]. In the present investigation dependence of reception in the Cl--ionophore site on the GABA receptor was studied on models used previously.

Biotransformation of a14C-hydrogenated phenazepam analog in inbred micein vivo

The aim of this investigation was to study excretion of a carbon 14-hydrogenated analog of phenazam (5-0-chlorophenyl-7-bromo-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one), synthesized by the authors, which was found, when compared with phenazepam itself, to induce a much weaker degree of muscle relaxation and ataxia and excretion of its metabolites. Inbred lines of mice were used with different oxidation phenotypes.

Analysis of the brain ACTH-immunoreactive peptide spectrum in inbred mice

Mice of the BALB/c (C) and C57BL/6 (B6) strains, characterized by high and low emotionality respectively in open field tests, have been shown to differ considerably in both the initial level and the time course of changes in the plasma ACTH concentration after exposure to stress in an open field and after administration of a benzodiazepine tranquilizer. The ACTH concentration in the pituitary gland of animals of these lines also differs. The ACTH molecule is known to contain regions with neurotropic activity. It can therefore be postulated that differences in the level of this hormone and the products of its bioconversion in the brain are an essential factor in the mechanisms of formation of the hereditary features of emotional behavior. In this first stage of this investigation, represented in this paper and undertaken to test this hypothesis, spectra of ACTH-immunoreactive peptides were studied in chromatographic fractions of an acid brain extract as well as in the blood plasma of mice belonging to B6 and C lines and their hybrids. The peptides were determined by radioimmunoassay.

Effect of phenazepam on plasma acth level of inbred mice exposed to stress

Benzodiazepine tranquilizers, phenazepam and diazepam, given to B6 mice had a mainly sedative effect, whereas given to C mice in low doses they had an activating effect [3, 4]. It has also been observed that B6 and C mice differ considerably both in the initial plasma ACTH level and in the time course of its changes after handling in the OF test [7]. (C57BL/ 6 • BALB/c)F, hybrids (F,) inherited investigative behavior in OF and a high ACTH level, characteristic of the parental B6 strain [3, 7].

Genetic control of the plasma ACTH level in mice

Experiments were carried out on male C57BL/6 (B6) and BALB/c (C) mice from the Stolbovaya nursery, Academy of Medical Sciences of the USSR, and reciprocal FI, F2, and FIx C hybrids, obtained in the laboratory, weighing 18-20 g; the animals were kept on a standard diet with 12 h daylight and 12 h darkness, i0 in a cage at a time, in a separate room in the animal house for 1 month before the experiment began.

Enzymatic model of the pharmacokinetics of phenazepam in the mouse organism

In the study of the metabolism of phenazepam (I) in the rat and mouse organism, we discovered [i] that it is practically identical. However, the quantitative aspects of this process differ. In the mouse organism the heterocyclic ring is intensively oxidized, and the benzdiazepine ring is narrowed to a quinazoline ring. In rats the basic pathway of the metabolism of I is the oxidation of the aromatic rings. It was also noted [2] that the experimental animals differ in activity of the enzymes catalyzing the oxidation of I.