ReviewAbuse and dependence liability of benzodiazepine-type drugs: GABAA receptor modulation and beyond
Section snippets
GABAA receptor modulators
Sedative/hypnotic drugs include those that are typically considered to be tranquilizers such as the barbiturates, benzodiazepines, and newer non-benzodiazepines. Clinically, these drugs are prescribed as anxiolytics, sedatives, anticonvulsants, and muscle relaxants, and share in common an ability to interact with the GABAA receptor (Bateson, 2004, Saunders and Ho, 1990). Barbiturates and benzodiazepine-type drugs are positive allosteric modulators of the receptor complex. They each bind to a
Behavioral effects of benzodiazepine-type drugs
Benzodiazepines were developed in the 1960s in response to a need for safe and effective anxiolytics. Barbiturates had lost favor as anxiolytics and anticonvulsants due to their low therapeutic index and high abuse potential (Morgan, 1990). The successor to the barbiturates, meprobamate, met a similar demise as reports of overuse and illicit diversion gradually negated its clinical usefulness and popularity (Littrell et al., 1993). The introduction of meprobamate, however, was the beginning of
Behavioral determinants of abuse and dependence liability
Drug seeking and drug taking behavior together is a complex phenomenon comprised of discrete behavioral components. The most likely property of a compound that predicts inappropriate use is the degree to which the compound has reinforcing effects. A drug is said to have reinforcing effects if its presentation increases the probability of subsequent responses to produce it. The study of the reinforcing effects of drugs has been an important emphasis of drug abuse research for decades, and the
GABAA receptor contribution to abuse and dependence liability
Recently, selective pharmacological tools have been developed that allow investigators to probe the GABAA receptor mechanisms underlying behaviors engendered by benzodiazepine-type drugs (Dawson et al., 2005). For example, although the hypnotic benzodiazepine-type drugs zolpidem and zaleplon interact with the benzodiazepine-binding site on the GABAA receptor, they enhance GABA-mediated chloride currents in recombinant GABAA receptors containing α1 subunits more selectively than those containing
Neuroadaptations following benzodiazepine administration: what is the biochemical basis of abuse-related effects?
Recent research efforts have been aimed at delineating the GABAA receptor mechanisms that underlie benzodiazepine-type drug-induced behavior, but relatively little is known about the downstream events that occur between allosteric modulation of the receptor by these drugs and the subsequent behavioral outcome. With respect to their abuse potential, the neurochemical, cellular, and molecular sequelae of events that occur following administration of benzodiazepine-type drugs are largely and
Summary and conclusions
Of the diverse types of ligands that act at the GABAA receptor, the benzodiazepines and related drugs are unique in having widespread clinical use and the liability for abuse and dependence. Laboratory findings suggest that benzodiazepine-type drugs have reinforcing effects both in human and non-human subjects, and recent epidemiological data suggests that abuse of benzodiazepine-type drugs may be on the rise.
Recent research has begun to explore the role of GABAA receptor subtypes in the
Acknowledgment
Preparation of this manuscript was supported by U.S.P.H.S. grants DA023659, DA11792, and RR00168.
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2021, Drug and Alcohol DependenceCitation Excerpt :More directly, a recent in vitro model of tolerance did not clearly demonstrate changes associated with the α5GABAA subtype, either with receptor expression or downstream mechanisms (Foitzick et al., 2020), indicating a clear need for further investigation under a broader range of conditions. Physical dependence following chronic BZ exposure is a major impediment to use of these drugs as pharmacotherapies (Griffiths and Weerts, 1997; Licata and Rowlett, 2008). Moreover, physical dependence likely contributes to ongoing misuse/abuse of BZs, because drug taking may come to be maintained by the alleviation of withdrawal (i.e., negative reinforcement) and avoidance of detoxification may be a major reason for resistance to drug abstinence as well as high relapse rates (O’Brien, 2005).