Advances in the understanding of the pharmacological mechanisms mediating effects of sedative, hypnotic, and anxiolytic medications began with the discovery of the GABAA benzodiazepine receptor complex (Squires and Brastrup 1977), the predominant inhibitory receptor in the central nervous system. It is a ligand-gated ion channel, which is activated by the neurotransmitter GABA. Activation leads to increase in Cl ion influx into the neuron and hyperpolarization of the neuronal membrane. As a result, the threshold required for the excitatory neurotransmitter to depolarize the membrane and produce an action potential is increased (i.e., GABA inhibits "excitability" of neuronal membranes). The GABAA receptor has binding sites for GABA, as well as regulatory sites for benzodiazepines, barbiturates, neurosteroids, anesthetics, anticonvulsants, and ethanol (Mohler et al. 2002) (Figure 16–1). There is considerable evidence that all sedative-hypnotics and alcohol interact with the GABAA receptor and that inhalants that are subject to abuse (various volatile organic compounds present in fuels, solvents, and cleaning products) may have similar mechanisms (Whiting 2003). The exact neural mechanism of each class of sedative-hypnotics is not well understood, but considering the similarities in behavioral and physiological effects of these drugs, it is reasonable to assume that physiological dependence and abuse liability associated with these agents is related to the changes occurring in the GABAergic receptor system.

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FIGURE 16–1. Schematic representation of the GABAA receptor complex.(A) Each GABAA receptor contains five transmembrane subunits arranged in a circle around the channel. Many different subunits have been identified to date, which are grouped into several classes. Most receptors include two subunits, two subunits, and a , , , , or subunit (Mohler et al. 2002). (B) View from the extracellular space of the most commonly encountered receptor subtype with the location of the benzodiazepine and low-affinity GABA sites. This receptor has high affinity for benzodiazepines, mediating its sedative, amnestic, anticonvulsant, and reinforcing effects. It also has a high affinity site for flumazenil and zolpidem. BZ = benzodiazepine; Cl = chloride ion; GABA = -aminobutyric acid.
Table Reference Number
TABLE 16–2. Pharmacological effects associated with specific subunits and receptor subunit selectivity for specific pharmacological agents


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