1 Institute of Pharmacology, Russian Academy of Medical Sciences, Moscow, Russia
2 Department of Human Physiology, Medical Academy, Lublin, Poland
One of the most important evolutionary factors of adaptation to environmental stress is anxiety. In outbred population this parameter has a great variability, dependent on genetically controlled differences in types of stress responses. Therefore, it should be taken into account when pharmacological correction is to be made. The major aim of this study was to evaluate effects of new benzodiazepin Hydazepam (Hyd) and Alprazolam (Alp) on the behaviour of two strains of mice: Balb/c and C57Bl/6 with different hereditary types of emotional stress reactions (ESR) in "unescapable" (open-field test) and "escapable" (elevated plus maze test) stress.
It was shown that behavioural effects of both drugs in "unescapable" stress in mice with "passive" type of ESR (Balb/c strain) were characterised by a bell-shaped dose-effect dependence with maximum activatory effect at 2-2.5 mg/kg (for Hyd) and at 0.5 mg/kg (for Alp). The differences between two drugs were displayed first of all in the width of active dose range. Further increase in active doses induced sedation. In the same test in animals with "active" type of ESR (C57Bl/6 strain) both drugs induced sedative activity, however, for Hyd some low doses were revealed which produced no sedation. Under conditions of "escapable" stress in Balb/c mice the revealed continuum of behavioral activity was interpreted as: (1) anxiolityc effect with activatory component (1st stage), (2) anxiolytic effect with sedative component (2nd stage), and (3) sedative activity (3rd stage). The effect on the 1st stage coincided with the ascending part of bell-shaped dependence in open-field test. The 2nd stage of activity coincided with the descending part of this dependence. Behavioural analysis of these different kinds of activity with RO15-1788 (10 mg/kg) has shown that anxiolytic-activatory effects of both drugs were not blocked by benzodiazepine receptor antagonist. On the contrary, their anxiolytic-sedative and sedative effects were partly or completely reversed by this compound. In C57Bl/6 mice both drugs only diminished the total locomotory activity in this test without significant changes of time in open arms. This sedation was also completely blocked by RO15-1788.
Summarising the data obtained in our experiments we can conclude, that (1) the formation of anxiolytic or sedative effects of benzodiazepine tranquilizers in varying stress situations depends on hereditary type of ESR, (2) the anxiolytic effect itself consists of minimum two different variants - with activatory and sedative components, (3) using the benzodiazepine tranquilizers of new generation like Hyd and its analogues we are able to detect the selective anxiolytic-activatory effect without sedation, (4) the continuum of benzodiazepine anxiolytic effects is mediated only partly through classic benzodiazepine receptor, (5) such drugs as Hyd and its analogues show the best promises for stress correction in outbred population.