THE EFFECTS OF DRUGS ACTING AT GABA-BENZODIAZEPINE-BARBITURATE RECEPTOR COMPLEX ON THE BEHAVIOR OF SLEEP-DERIVED MICE

The effects of the benzodiazepine receptor agonist diazepam, the benzo diazepine receptor antagonist flumazenil and the benzodiazepine recept or inverse agonist -8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-[1, 5-a] [1-4] benzodiazepine-3-carboxylate (RO 15-4513) on the locomotor activity and the behaviour of animals in the plus-maze test were studi ed in sleep-deprived mice. The effects of convulsants acting at GABA-b enzodiazepine-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 dose s) or inhibited (in high doses) locomotions of control animals. The in hibition of locomotor activity by these drugs was greater in sleep-dep rived 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 incr ease in the percentage of entries onto and the percentage of time spen t on the open arms of the plus-maze. In contrast, in sleep-deprived an imals, diazepam did not induce anxiolytic action al any dose tested. I n the highest dose (2.5 mg/kg) diazepam produced a sedative effect tha t was reflected by a decrease in the total number of entries made onto the open and into the closed arm!; of the plus-maze. The convulsive a ctions of bicuculline (2.0-4.0 mg/kg) and picrotoxin (2.5-4.0 mg/kg) w ere 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 depr ivation 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 sa me time sleep deprivation induces a hyposensitivity of mice to the anx iolytic 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-deprive d mice might be due to the alterations in the function of GABA-benzodi azepine-barbiturate complex induced by sleep deprivation.