Drugs modulating γ-aminobutyric acid (GABA) transmission via the benzodiazepine (BZ) site on the γ-aminobutyric acid type A (GABAA) receptor have been in widespread use for more than 40 years to treat anxiety, epilepsy, and sleep disorders. These drugs have been shown to be safe, well tolerated, and effective although the mechanism by they produce a myriad of pharmacologic effects remains elusive. In recent years it has been discovered that, although the GABAA receptor is widely distributed in the brain, the substructure and composition of the receptor differs from between brain regions. Termed “GABAA receptor subtypes” their discovery leads to speculation that different subtypes may mediate specific effects of BZs such as anxiety or sedation. The phenotypic analysis of transgenic knock-in and knock-out mice in which particular GABAA receptors were rendered insensitive to the effects of BZ while others were unaffected confirmed this speculation. Subsequently, subtype-specific GABAA ligands were developed that, for example, retained the anxiolytic effects of BZs but were devoid of their sedative effects. Therefore, it may be possible to develop effective anxiolytic compounds that have a much reduced side-effect profile compared with existing drugs.

When benzodiazepines (BZs) supplanted barbiturates as a favored, safer treatment for anxiety and sleep disorders in the 1960s, the abuse liability and dependence potential of these drugs were little understood. Widespread recognition of the difficulty of stopping use of chronically taken BZs emerged through the popular press in the late 1970s, which resulted in reluctance to prescribe these otherwise clinically useful compounds. Evolution of the understanding of the biochemical basis for BZ effects in the 1980s and 1990s, coupled with regulatory emphasis on collection of data used in legal scheduling decisions, made possible a targeted search for drugs that would provide effective treatment for anxiety disorders in the absence of abuse liability or dependence potential. Compounds that have selective efficacy at subtypes of the γ-aminobutyric acid type A receptor, are active in preclinical anxiolytic screens, but negative in preclinical studies of behavior relevant to evaluation of abuse liability appear to be one promising means for achieving this end.

Benzodiazepines (BZs) are clinically used as anxiolytic, hypnotic, anticonvulsant, and antispasmodic drugs. Research using transgenic mouse models has suggested that the effects of BZs involve multiple subtypes of the γ-aminobutyric acid type A (GABAA) receptor, identified by specific α subunits (α1, α2, α3, α5). This review discusses the experimental uses of β-carboline-3-carboxylate-t-butyl ester (βCCT), a drug that binds preferentially to the GABAA α1 subtype but exerts no action (ie, is a pharmacologic antagonist at the GABAA α1 subtype receptor). βCCT blocks the anxiolytic-like effects of BZs, although studies in primates suggests this antagonism may reflect multiple receptor populations. βCCT antagonized the ataxic but not muscle relaxant effects of BZs, a finding that implicates the GABAA α1 subtype receptor in ataxia but not muscle relaxation. The potential clinical utility of βCCT is discussed, both in terms of treatment (ie, hepatic encephalopathy) and as a diagnostic imaging agent. Altogether, these results indicate that subtype-selective antagonists represent a useful approach to studying receptor mechanisms underlying the behavioral effects of BZ-type drugs.

Anxiety disorders are common and often disabling. They fall into five main categories: panic disorder, social anxiety disorder, generalized anxiety disorder, obsessive-compulsive disorder and posttraumatic stress disorder, each of which have characteristic symptoms and cognitions. All anxiety disorders respond to drugs and psychological treatments. This review will focus on drug treatments. Recent research has emphasized the value of antidepressants especially the selective serotonin reuptake inhibitors, benzodiazepines, and related sedative-like compounds. The common co-existence of depression with all of the anxiety disorders means that the selective serotonin reuptake inhibitors are now generally considered to be the first-line treatments but the benzodiazepines have some utility especiaRy in promoting sleep and working acutely to reduce extreme distress.