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The GABAA receptor is the major molecular target for the action of many drugs in the brain

Among these are benzodiazepines, intravenous and volatile anesthetics and possibly ethanol. Benzodiazepine receptor-binding sites copurify with the GABA-binding sites [13]. In addition, benzodiazepine receptors are immunoprecipitated with antibodies that were developed to recognize the protein containing the GABA-binding site [14]. This indicates that the benzodiazepine receptor is an integral part of the GABAA receptor—Cl− channel complex.

Benzodiazepine agonists represent the newest group of agents in the general class of depressant drugs, which also includes barbiturates, that show anticonvulsant, anxiolytic and sedative—hypnotic activity. Well-known examples include diazepam and chlordiazepoxide, which often are prescribed for their anti-anxiety effects [1]. The mechanism of action of benzodiazepine agonists is to enhance GABAergic transmission. From electrophysiological studies, it is known that these benzodiazepines increase the frequency of channel opening in response to GABA, thus accounting for their pharmacological and therapeutic actions [8]. In addition, the benzodiazepine site is coupled allosterically to the barbiturate and picrotoxin sites [2]. Benzodiazepine receptors are heterogeneous with respect to affinity for certain ligands. A wide variety of nonbenzodiazepines, such as the β-carbolines, cyclopyrrolones and imidazopyridines, also bind to the benzodiazepine site.

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Barbiturates comprise another class of drugs commonly used therapeutically for anesthesia and control of epilepsy. Phenobarbital and pentobarbital are two of the most commonly used barbiturates. Phenobarbital has been used to treat patients with epilepsy since 1912. Pentobarbital is also an anticonvulsant, but it has sedative side effects. Barbiturates at pharmacological concentrations allosterically increase binding of benzodiazepines and GABA to their respective binding sites [2]. Measurements of mean channel open times show that barbiturates act by increasing the proportion of channels opening to the longest open state (9 msec) while reducing the proportion opening to the shorter open states (1 and 3 msec), resulting in an overall increase in mean channel open time and Cl− flux [8].

Channel blockers, such as the convulsant compound picrotoxin, cause a decrease in mean channel open time. Picrotoxin works by preferentially shifting opening channels to the briefest open state (1 msec). Thus, both picrotoxin and barbiturates appear to act on the gating process of the GABAA receptor channel, but their effects on the open states are opposite to each other. Experimental convulsants like pentylenetetrazol and the cage convulsant t-butyl bicyclophosphorothionate (TBPS) act in a manner similar to picrotoxin, preventing Cl− channel permeability. The antibiotic penicillin is a channel blocker with a net negative charge. It blocks the channel by interacting with the positively charged amino acid residues within the channel pore, consequently occluding Cl− passage through the channel [8].

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There have been numerous studies on the role of GABAA receptors in anesthesia. A considerable amount of evidence has been compiled to suggest that general anesthetics, including barbiturates, volatile gases, steroids and alcohols, enhance GABA-mediated Cl− conductance. A proper assessment of this phenomenon requires not only a behavioral assay of anesthesia but also in vitro models for the study of receptor function. In this regard, not only electrophysiological methods but also neurochemical measurements of Cl− flux and ligand binding have been useful. For example, a strong positive correlation exists between anesthetic potencies and the stimulation of GABA-mediated Cl− uptake. This is seen with barbiturates and anesthetics in other chemical classes [3].

Comparison of ligand-gated ion channels that vary in sensitivity to anesthetic modulation, using the chimera and site-directed mutagenesis approach, has identified two amino acids in the membrane-spanning domains that are critical for anesthetic sensitivity [14a]. Direct evidence of ethanol augmentation of GABAA receptor function, measured either by electrophysiological techniques or agonist-mediated Cl− flux, has been reported [3,15]. The similarity between the actions of ethanol and sedative drugs such as benzodiazepines and barbiturates that enhance GABA action suggests that ethanol may exert some of its effects by enhancing the function of GABAA receptors. Ethanol potentiation of GABAA receptor function appears to be dependent upon the cell type tested and the method of assay. This suggests that the ethanol interaction may be specific for certain receptor subtypes and/or that it may be an indirect action [3].

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