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CHAPTER 22 Sedative-Hypnotic Drugs 387

Cl – GABA Receptor Heterogeneity &
GABA
GABA Pharmacologic Selectivity
β
β α α Benzodiazepines Studies involving genetically engineered (“knockout”)
Flumazenil rodents have demonstrated that the specific pharmacologic
Extracellular
Zolpidem
actions elicited by benzodiazepines and other drugs that
γ modulate GABA actions are influenced by the composition
of the subunits assembled to form the GABA A receptor. Ben-
zodiazepines interact primarily with brain GABA A receptors
in which the α subunits (1, 2, 3, and 5) have a conserved
histidine residue in the N-terminal domain. Strains of mice,
in which a point mutation has been inserted converting his-
tidine to arginine in the α1 subunit, show resistance to both
Barbiturates the sedative and amnestic effects of benzodiazepines, but
Intracellular anxiolytic and muscle-relaxing effects are largely unchanged.
Ion channel
These animals are also unresponsive to the hypnotic actions
of zolpidem and zaleplon, drugs that bind selectively to
GABA A receptors containing α1 subunits. In contrast, mice
FIGURE 22–6 A model of the GABA A receptor-chloride ion with selective histidine-arginine mutations in the α2 or α3
channel macromolecular complex. A hetero-oligomeric glycoprotein, subunits of GABA A receptors show selective resistance to the
the complex consists of five or more membrane-spanning subunits. antianxiety effects of benzodiazepines. Based on studies of
Multiple forms of α, β, and γ subunits are arranged in different pen- this type, it has been suggested that α1 subunits in GABA A
tameric combinations so that GABA A receptors exhibit molecular receptors mediate sedation, amnesia, and ataxic effects of
heterogeneity. GABA appears to interact at two sites between α and benzodiazepines, whereas α2 and α3 subunits are involved
β subunits triggering chloride channel opening with resulting mem-
brane hyperpolarization. Binding of benzodiazepines and the newer in their anxiolytic and muscle-relaxing actions. Other muta-
hypnotic drugs such as zolpidem occurs at a single site between α and tion studies have led to suggestions that an α5 subtype is
γ subunits, facilitating the process of chloride ion channel opening. The involved in at least some of the memory impairment caused
benzodiazepine antagonist flumazenil also binds at this site and can by benzodiazepines. It should be emphasized that these stud-
reverse the hypnotic effects of zolpidem. Note that these binding sites ies involving genetic manipulations of the GABA A receptor
are distinct from those of the barbiturates. (See also text and Box: The utilize rodent models of the anxiolytic and amnestic actions
Versatility of the Chloride Channel GABA Receptor Complex.) of drugs.

Benzodiazepines appear to increase the efficiency of GABAergic
synaptic inhibition. The benzodiazepines do not substitute for C. Benzodiazepine Binding Site Ligands
GABA but appear to enhance GABA’s effects allosterically without The components of the GABA receptor-chloride ion channel mac-
A
directly activating GABA receptors or opening the associated romolecule that function as benzodiazepine binding sites exhibit
A
chloride channels. The enhancement in chloride ion conductance heterogeneity (see Box: The Versatility of the Chloride Channel
induced by the interaction of benzodiazepines with GABA takes GABA Receptor Complex). Three types of ligand-benzodiazepine
the form of an increase in the frequency of channel-opening events. receptor interactions have been reported: (1) Agonists facilitate
Barbiturates also facilitate the actions of GABA at multiple sites GABA actions, and this occurs at multiple BZ binding sites in the
in the CNS, but—in contrast to benzodiazepines—they appear to case of the benzodiazepines. As noted above, the nonbenzodiaz-
increase the duration of the GABA-gated chloride channel openings. epines zolpidem, zaleplon, and eszopiclone are selective agonists
At high concentrations, the barbiturates may also be GABA-mimetic, at the BZ sites that contain an α1 subunit. Endogenous agonist
directly activating chloride channels. These effects involve a binding ligands for the BZ binding sites have been proposed, because
site or sites distinct from the benzodiazepine binding sites. Barbitu- benzodiazepine-like chemicals have been isolated from brain tissue
rates are less selective in their actions than benzodiazepines, because of animals never exposed to these drugs. Nonbenzodiazepine mol-
they also depress the actions of the excitatory neurotransmitter ecules that have affinity for BZ sites on the GABA receptor have
A
glutamic acid via binding to the AMPA receptor. Barbiturates also also been detected in human brain. (2) Antagonists are typified by
exert nonsynaptic membrane effects in parallel with their effects on the synthetic benzodiazepine derivative flumazenil, which blocks
GABA and glutamate neurotransmission. This multiplicity of sites of the actions of benzodiazepines, eszopiclone, zaleplon, and zolpidem,
action of barbiturates may be the basis for their ability to induce full but does not antagonize the actions of barbiturates, meprobamate,
surgical anesthesia (see Chapter 25) and for their more pronounced or ethanol. Certain endogenous neuropeptides are also capable
central depressant effects (which result in their low margin of safety) of blocking the interaction of benzodiazepines with BZ binding
compared with benzodiazepines and the newer hypnotics. sites. (3) Inverse agonists act as negative allosteric modulators of