Primary Mechanism of Action of Benzodiazepines
Benzodiazepines exert their primary mechanism of action by binding to GABA-A receptors in the central nervous system, where they enhance the inhibitory effects of gamma-aminobutyric acid (GABA), the brain's primary inhibitory neurotransmitter, thereby decreasing neuronal excitability. 1, 2, 3
Core Mechanism
- Benzodiazepines do not directly activate GABA-A receptors but rather act as positive allosteric modulators that require the presence of GABA to function 4
- When benzodiazepines bind to their specific site on the GABA-A receptor complex, they increase the affinity of the GABA receptor for its ligand (GABA), thereby augmenting the inhibitory effect of a given concentration of GABA 5
- This binding occurs at stereospecific receptors located at several sites within the central nervous system, with the benzodiazepine receptor anatomically in close association with GABA receptors on the same supramolecular protein complex 6, 5
Molecular Details
- The GABA-A receptor is an ionotropic receptor, and benzodiazepine binding facilitates the action of GABA as an inhibitory neurotransmitter 3, 4
- Benzodiazepines activate GABA-A receptors by enhancing the activity of GABA, reducing the excitability of the central nervous system 2
- Key residues within the N-terminal region of alpha subunits of GABA-A receptors (such as α1, α2, α3, and α5 subunits) are critical for benzodiazepine binding and action 2, 7
Clinical Effects Resulting from This Mechanism
The enhancement of GABAergic inhibition produces all the characteristic clinical effects of benzodiazepines:
- Sedation and hypnosis 4
- Anxiolysis (decreased anxiety) 4
- Anticonvulsant activity 4
- Muscle relaxation (centrally mediated) 3, 4
- Anterograde amnesia 4
- Dose-related central nervous system depression ranging from mild impairment of task performance to hypnosis 6
Important Caveats
- While the primary mechanism involves the nanomolar-range binding at the classical benzodiazepine site, evidence suggests benzodiazepines may also act through a secondary mechanism at micromolar concentrations involving specific residues in the second transmembrane domains (TM2) of GABA-A receptor subunits 7
- The exact molecular mechanism by which benzodiazepines modulate GABA-A receptors remains incompletely understood, though the functional outcome (enhanced GABAergic inhibition) is well-established 6