The components of the GABAA receptor-chloride ion channel macromolecule that function as benzodiazepine binding sites exhibit heterogeneity (see Box: The Versatility of the Chloride Channel GABA Receptor Complex). Three types of ligand-benzodiazepine receptor interactions have been reported: (1) Agonists facilitate GABA actions, and this occurs at multiple BZ binding sites in the case of the benzodiazepines. As noted above, the nonbenzodiazepines zolpidem, zaleplon, and eszopiclone are selective agonists at the BZ sites that contain an α1 subunit. Endogenous agonist ligands for the BZ binding sites have been proposed, because benzodiazepine-like chemicals have been isolated from brain tissue of animals never exposed to these drugs. Nonbenzodiazepine molecules that have affinity for BZ sites on the GABAA receptor have also been detected in human brain. (2) Antagonists are typified by the synthetic benzodiazepine derivative flumazenil, which blocks the actions of benzodiazepines, eszopiclone, zaleplon, and zolpidem, but does not antagonize the actions of barbiturates, meprobamate, or ethanol. Certain endogenous neuropeptides are also capable of blocking the interaction of benzodiazepines with BZ binding sites. (3) Inverse agonists act as negative allosteric modulators of
The GABAA-chloride channel macromolecular complex is one of the most versatile drug-responsive machines in the body. In addition to the benzodiazepines, barbiturates, and the newer hypnotics (eg, zolpidem), many other drugs with central nervous system effects can modify the function of this important ionotropic receptor. These include alcohol and certain intravenous anesthetics (etomidate, propofol) in addition to thiopental. For example, etomidate and propofol (see Chapter 25) appear to act selectively at GABAA receptors that contain α2 and α3 subunits, the latter suggested to be the most important with respect to the hypnotic and muscle-relaxing actions of these anesthetic agents. The anesthetic steroid alphaxalone is thought to interact with GABAA receptors, and they may also be targets for some of the actions of volatile anesthetics (eg, halothane). Most of these agents facilitate or mimic the action of GABA. However, it has not been shown that all these drugs act exclusively by this mechanism. Other drugs used in the management of seizure disorders indirectly influence the activity of the GABAA-chloride channel macromolecular complex by inhibiting GABA metabolism (eg, vigabatrin) or the reuptake of the transmitter (eg, tiagabine). Central nervous system excitatory agents that act on the chloride channel include picrotoxin and bicuculline. These convulsant drugs block the channel directly (picrotoxin) or interfere with GABA binding (bicuculline).
GABA-receptor function (see Chapter 1). Their interaction with
BZ sites on the GABAA receptor can produce anxiety and seizures, an action that has been demonstrated for several compounds, especially the β-carbolines, eg, n-butyl-β-carboline-3-carboxylate (β-CCB). In addition to their direct actions, these molecules can block the effects of benzodiazepines. The physiologic significance of endogenous modulators of the functions of GABA in the CNS remains unclear. To date, it has not been established that the putative endogenous ligands of BZ bind ing sites play a role in the control of states of anxiety, sleep patterns, or any other characteristic behavioral expression of CNS function.