The Effects of Drugs Acting at GABA‐Benzodiazepine‐Barbiturate Receptor Complex on the Behaviour of Sleep‐Deprived Mice

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Abstract
The effects of the benzodiazepine receptor agonist diazepam, the benzodiazepine receptor antagonist flumazenil and the benzodiazepine receptor inverse agonist ethyl-8-azido-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo-[1, 5-a] [1-4] benzo-diazepine-3-carboxylate (RO 15-4513) on the locomotor activity and the behaviour of animals in the plus-maze test were studied in sleep-deprived mice. The effects of convulsants acting at GABA-benzodiazepine-barbiturate receptor complex-bicuculline, picrotoxin and pentylenetetrazole, were also studied. Sleep deprivation of mice for 24 hr using the platform technique caused behavioural excitation that was reflected by an increase in the locomotor activity. Administration of diazepam (0.5 and 2.0 mg/kg), flumazenil (5.0 and 10.0 mg/kg) and RO 15-4513 (1.0, 2.0 and 3.0 mg/kg) either did not affect (in low doses) or inhibited (in high doses) locomotions of control animals. The inhibition of locomotor activity by these drugs was greater in sleep-deprived animals. In the plus-maze test, diazepam in a dose of 2.5 mg/kg had an anxiolytic effect in control mice that was reflected by an increase in the percentage of entries onto and the percentage of time spent on the open arms of the plus-maze. In contrast, in sleep-deprived animals, diazepam did not induce anxiolytic action at any dose tested. In the highest dose (2.5 mg/kg) diazepam produced a sedative effect that was reflected by a decrease in the total number of entries made onto the open and into the closed arms of the plus-maze. The convulsive actions of bicuculline (2.0–4.0 mg/kg) and picrotoxin (2.5–4.0 mg/kg) were considerably more pronounced in sleep-deprived mice as compared to control animals. The effect of pentylenetetrazole (60–100 mg/kg) was not changed in sleep-deprived mice. These data suggest that sleep deprivation induced a sensitization of mice to the motor depressant effect of benzodiazepine receptor agonists, antagonists and inverse agonists and to the convulsive action of bicuculline and picrotoxin. At the same time sleep deprivation induces a hyposensitivity of mice to the anxiolytic effect of diazepam. It is proposed that the hyposensitivity to the anxiolytic effect of diazepam as well as the hypersensitivity to the convulsions induced by bicuculline and picrotoxin in sleep-deprived mice might be due to the alterations in the function of GABA-benzodiazepine-barbiturate complex induced by sleep deprivation.