The influence of midazolam on active avoidance retrieval and acquisition rate in rats.

The purpose of the present study was to examine the influence of midazolam on the retrieval and acquisition rate of two-way active avoidance in rats. In the schedule 2 x 100 trials, the effects of midazolam (0.5-5.0 mg/kg), benzodiazepine binding site antagonist flumazenil (2.5-10.0 mg/kg), specific antagonist of GABA(A) receptor, bicuculline (0.5-4.0 mg/kg), and the blocker of GABA(A) receptor containing Cl(-) channels, picrotoxin (1.0-5.0 mg/kg), on the second day retrieval of avoidance performance were investigated, as well as the influence of the used blockers of GABA(A) receptor function on midazolam effects. Furthermore, the effect of midazolam (1.0 mg/kg) on acquisition rate in the 5 x 50 schedule, as well as the effects of third day treatment changing in that paradigm, was examined. Throughout the study, drugs were given intraperitoneally, 30 min before testing. Midazolam at the dose of 1.0 mg/kg facilitated avoidance retrieval, whereas flumazenil and bicuculline did not significantly change behavior. Picrotoxin (5.0 mg/kg) diminished performance. All three kinds of blockers used abolished facilitatory action of midazolam, confirming GABAergic mediation of the effect of benzodiazepine. Midazolam (1.0 mg/kg) increased acquisition rate during five consecutive days relative to saline, but without significant effect on the first day acquisition. In the case of third day changing of treatments, the intersection of regression rate lines was detected. Results from active avoidance paradigm experimentally support the findings from human studies that in certain circumstances, benzodiazepines, potentiating GABAergic neurotransmission, could produce retrieval-enhancing effects in memory tasks.

The influence of midazolam and flumazenil on rat brain slices oxygen consumption.

This study investigated the impact of benzodiazepine receptor agonist, midazolam and antagonist, flumazenil, on the rat frontal cortex slices oxygen consumption (QO(2)), in presence and absence of gamma-aminobutyric acid (GABA). QO(2) was polarographically determined, using the biological oxygen monitor. As it was previously shown, GABA on its own decreases QO(2) moderately. Midazolam decreased QO(2) at 1.0mg/kg, whereas flumazenil had no effect. In combination with per se ineffective GABA (10(-6)mol/l), flumazenil showed respiratory depressant action, presumably revealing partial agonistic activity at some of GABA(A) receptor subtypes. However, it completely antagonized effects of midazolam on QO(2), on its own and in presence of GABA. Our results show that in vivo well-established effects of midazolam on cerebral metabolic activity could be reproduced in in vitro settings. Moreover, flumazenil antagonized this action, indicating the role of GABA(A)-benzodiazepine receptor complex activation in QO(2) regulation.

Gaba-benzodiazepine receptor complex in brain oxidative metabolism regulation.

This study investigated the impact of modulating the gamma-aminobutyric acid(A) (GABA)(A)-benzodiazepine receptor complex activity on the rat frontal cortex slices oxygen consumption (QO(2)), polarographically determined using the biological oxygen monitor. Throughout the study, diazepam, flumazenil and picrotoxin were administered i.p. 30 min before sacrificing animals and obtaining slice preparations, while GABA was added directly into the medium in the reaction chamber. GABA decreased QO(2) in concentrations of 5 x 10(-4), 10(-2) and 5 x 10(-2)mol l(-1), while 10(-5) and 10(-6)mol l(-1) GABA had no effect, as well as diazepam, flumazenil and picrotoxin. All diazepam doses (1, 2.5 and 5 mg kg(-1)) increased action of 5 x 10(-4)mol l(-1) GABA, whereas 2.5 mg kg(-1) dose amplified the effect of 10(-6)mol l(-1) GABA. Flumazenil and picrotoxin (5 mg kg(-1) both) blocked diazepam's effects. Flumazenil augmented 10(-6)mol l(-1) GABA effects, while picrotoxin and flumazenil abolished the effects of 5 x 10(-4)mol l(-1) GABA. To our knowledge, this is the first study to examine the influence of modulation of GABA(A)-benzodiazepine receptor function on cerebral metabolism of oxygen in in vitro settings. The results are in accordance with those obtained in numerous in vivo studies, pointing to the moderate level of influence of GABA(A)-benzodiazepine receptor complex on QO(2) regulation.