Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes

Abstract

GABA(A) (γ-aminobutyric acid, type A) receptors are a family of ligand-gated ion channels that are essential for the regulation of central nervous system function. Benzodiazepines - which non-selectively target GABA(A) receptors containing the α1, α2, α3 or α5 subunits - have been in clinical use for decades and are still among the most widely prescribed drugs for the treatment of insomnia and anxiety disorders. However, their use is limited by side effects and the risk of drug dependence. In the past decade, the identification of separable key functions of GABA(A) receptor subtypes suggests that receptor subtype-selective compounds could overcome the limitations of classical benzodiazepines; furthermore, they might be valuable for novel indications such as chronic pain, depression, schizophrenia, cognitive enhancement and stroke.

Figure 1. Pharmacological effects and distribution of GABA_A receptor α subunits in the mouse brain

The pie chart represents the approximate abundance of the GABA_A receptor subtypes that are known to exist in vivo. α1 is expressed in cortex, thalamus, pallidum and hippocampus. α2 is expressed in hippocampus, cortex, striatum, and nucleus accumbens (not shown). α3 is expressed in the cortex and the reticular nucleus of the thalamus, and α5 in the hippocampus and in deep layers of the cortex. The anti-hyperalgesic actions are mediated by spinal GABA_A receptors. Data in references ^{, –}. Immunohistochemical pictures are courtesy of Dr. Jean-Marc Fritschy, University of Zurich, and have been published in ref. . [CE: waiting to see if we need to apply for permission to use these]

Figure 2. Structures of allosteric GABA_A receptor modulators

A. Preclinical and clinically tested, binding or functionally subtype-selective positive allosteric modulators (agonists). B. Preclinical and clinically tested, binding or functionally subtype-selective negative allosteric modulators (inverse agonists).

Figure 3. GABA-evoked currents in human embryonic kidney 293 (HEK293)- cells

(A) GABA is applied to a cell expressing a GABA_A receptor subtype for the time indicated by the black horizontal bar resulting in a current symbolized by the blue trace. When GABA is applied in the presence of a positive allosteric modulator (PAM, BZ site agonist), the current is enhanced (orange trace). Negative allosteric modulators (NAM, BZ site inverse agonists) and neutral allosteric modulators (BZ site antagonists) either decrease (green trace) or have no effect (red trace) on the GABA-induced current. A subtype-selective modulation of the current is observed when GABA is applied in the presence of L-838,417 (B) or RO4938581 (C) to cells expressing various GABA_A receptors. Percent modulation of GABA-induced chloride currents is shown. The lack of modulation of α1-containing GABA_A receptors by L-838,417 is thought to be the basis for the lack of a sedative action of this compound in animals, whereas its partial positive allosteric modulatory (agonistic) action at α2-containing GABA_A receptors (and potentially α3-containing GABA_A receptors) is thought to be responsible for its anxiolytic-like action. Similarly, the lack of modulation of α1-containing GABA_A receptors by RO4938581 is thought to be – at least in part - the basis for the lack of a pro-convulsive potential of this drug; the cognition-enhancing effects are hypothesized to be mediated via its negative allosteric modulation (inverse agonism) at α5-containing GABA_A receptors. These illustrative traces are based on data in ^, .

Figure 4. GABA_A receptor subtypes in the mesolimbic dopaminergic systems involved in pathways of addiction

GABAergic neurons in the ventral tegmental area (VTA) express the α1 subunit, whereas dopaminergic neurons in the VTA predominantly express the α3 subunit. Binding of benzodiazepines to the α1-containing GABA_A receptors on GABAergic VTA neurons leads to a reduction of the activity of these cells, and thus reduced release of GABA, which results in a disinhibition of the dopaminergic VTA neurons and a resulting increase in DA release in the ventral striatum. In principle, benzodiazepines likely have functionally opposing actions via the α1-containing GABA_A receptors on GABAergic neurons and on α3-containing GABA_A receptors on the dopaminergic neurons of the VTA. However, the effect on the α1-containing GABA_A receptors on the dopaminergic neuron is functionally predominant.