Abuse and Dependence Liability of GABAA-Receptor Modulators

Ligands that act at γ-aminobutyric type A (GABAA) receptors, in particular the benzodiazepines and related drugs, have broad clinical use but also the liability for abuse and dependence. Recent epidemiological data suggest that abuse of benzodiazepine-type drugs may be on the upswing, with a shift from primary misuse of benzodiazepines by people in a therapeutic setting to use by younger people engaging in recreational abuse. Laboratory findings suggest that benzodiazepine-type drugs have reinforcing effects both in human and non-human subjects. However, benzodiazepine-type drugs appear to have lower reinforcing effectiveness compared to other drugs of abuse, such as psychomotor stimulants. Recent research has begun to explore the role of GABAA receptor subtypes in the reinforcing effects of benzodiazepine-type drugs, and unlike other behavioral effects (e.g., motor coordination deficits); reinforcing effects are not easily attributed to a single receptor subtype. Perhaps the most firm conclusion that can be made at this point is that stimulation of GABAA receptors containing α1 subunits (α1GABAA receptors) is not necessary for self-administration of benzodiazepine-type compounds. Benzodiazepine use also is associated with physical dependence, characterized by a withdrawal syndrome. In both human and non-human subjects, this withdrawal syndrome is considered to be intermediate in severity. Preliminary results suggest that compounds with selectivity for α2GABAA, α3GABAA, and/or α5GABAA receptors do not induce physical dependence. As with reinforcing effects, systematic studies with selective compounds having relatively high intrinsic efficacy at particular subtypes should shed light on theses important mechanistic issues.