Benzodiazepines appear to increase the efficiency of GABAergic synaptic inhibition. The benzodiazepines do not substitute for GABA but appear to enhance GABA’s effects allosterically without directly activating GABAA receptors or opening the associated chloride channels. The enhancement in chloride ion conductance induced by the interaction of benzodiazepines with GABA takes the form of an increase in the frequency of channel-opening events.
Barbiturates also facilitate the actions of GABA at multiple sites in the CNS, but—in contrast to benzodiazepines—they appear to increase the duration of the GABA-gated chloride channel openings. At high concentrations, the barbiturates may also be GABA-mimetic, directly activating chloride channels. These effects involve a binding site or sites distinct from the benzodiazepine binding sites. Barbiturates are less selective in their actions than benzodiazepines, because they also depress the actions of the excitatory neurotransmitter glutamic acid via binding to the AMPA receptor. Barbiturates also exert nonsynaptic membrane effects in parallel with their effects on GABA and glutamate neurotransmission. This multiplicity of sites of action of barbiturates may be the basis for their ability to induce full surgical anesthesia (see Chapter 25) and for their more pronounced central depressant effects (which result in their low margin of safety) compared with benzodiazepines and the newer hypnotics.
Studies involving genetically engineered (“knockout”) rodents have demonstrated that the specific pharmacologic actions elicited by benzodiazepines and other drugs that modulate GABA actions are influenced by the composition of the subunits assembled to form the GABAA receptor. Benzodiazepines interact primarily with brain GABAA receptors in which the α subunits (1, 2, 3, and 5) have a conserved histidine residue in the N-terminal domain. Strains of mice, in which a point mutation has been inserted converting histidine to arginine in the α1 subunit, show resistance to both the sedative and amnestic effects of benzodiazepines, but anxiolytic and muscle-relaxing effects are largely unchanged. These animals are also unresponsive to the hypnotic actions of zolpidem and zaleplon, drugs that bind selectively to GABAA receptors containing α1 subunits. In contrast, mice with selective histidine-arginine mutations in the α2 or α3 subunits of GABAA receptors show selective resistance to the antianxiety effects of benzodiazepines. Based on studies of this type, it has been suggested that α1 subunits in GABAA receptors mediate sedation, amnesia, and ataxic effects of benzodiazepines, whereas α2 and α3 subunits are involved in their anxiolytic and muscle-relaxing actions. Other mutation studies have led to suggestions that an α5 subtype is involved in at least some of the memory impairment caused by benzodiazepines. It should be emphasized that these studies involving genetic manipulations of the GABAA receptor utilize rodent models of the anxiolytic and amnestic actions of drugs.
C. Benzodiazepine Binding Site Ligands