GABA-induced depolarizing responses of the frog spinal cord can be either enhanced or antagonized by the benzodiazepine midazolam and the methylxanthine caffeine

Abstract

The isolated frog spinal cord was used as a test system to investigate the interactions of midazolam and caffeine with GABA-evoked responses recorded from dorsal afferent fibres. Midazolam was a potent stimulator ( ED 50 = 1 nM ) of GABA effectiveness on this preparation since the ED 50 value for GABA was nearly halved. The enhancing action of midazolam was apparently produced via activation of benzodiazepine receptor mechanisms with no detectable receptor cooperativity and with a rather high sensitivity to the selective benzodiazepine antagonist Ro 14–7437 (antagonist ED 50 = 2.5 nM ). Responses to glutamate, glycine or high K + were unchanged in midazolam solutions. When midazolam was applied in concentrations equal or larger than 100 nM, antagonism of GABA responses was evident. Caffeine (50 μM) also potentiated GABA responses through a mechanism distinct from benzodiazepine receptor activation as this action of caffeine was insensitive to Ro 14–7437. Mixtures of low doses of caffeine and midazolam frequently antagonized GABA responses. It is suggested that the blockade of GABA responses by caffeine-midazolam mixtures might account for the reversal of some behavioural actions of these substances even if they probably operate through separate pharmacological mechanisms.