ABSTRACT

Attempts in the early 1960s to delineate which areas of the central nervous system were involved in mediating the overt effects of the benzodiazepines proved less than equal to the task. The Roche group found that the specific γ-aminobutyric acid (GABA)antagonists, bicuculline and picrotoxin, behaved in a mutually antagonistic manner with the benzodiazepines to influence presynaptic inhibition, indicating that in some way GABAergic transmission was integral to their mechanism of action. The benzodiazepines could equally well be responsible for modulation of the underlying mechanism of primary afferent depolarisation or by interaction, in some way, with GABAergic transmission itself. The original 5-phenyl-1,4-benzodiazepines all appear to be agonists with similar efficacy: they potentiate GABAA receptor-activated currents by increasing the probability of channel opening in response to a given GABA stimulus. Partial agonists acting on the benzodiazepine binding site, with intermediate intrinsic activities between full agonists such as diazepam and antagonists, such as flumazenil, have been known for many years.