Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective GABA_A Receptor Modulators?

Figure 1

Representation of the GABA_A receptor structure. The inhibitory GABA_A receptor consists of five subunits that together form a ligand-gated chloride (Cl⁻) channel (a). When GABA binds (between the α and the β subunit of the GABA_A receptor), chloride ions flow into the neuron, resulting in a hyperpolarization of the cell membrane (a). Classical nonselective benzodiazepines allosterically enhance the inhibitory actions of GABA by binding between the α ₁, α ₂, α ₃, or α ₅ subunit and the γ subunit (b). Although the GABA_A receptor displays a large molecular heterogeneity depending on the subunit composition, the most common subtype is a pentamer with 2α, 2β, and 1γ subunit.