GABAergic Pharmacology
GABA as the brain's primary inhibitory neurotransmitter, GABA-A and GABA-B receptor pharmacology, and drugs that enhance inhibition.
GABA Synthesis and Metabolism
Gamma-aminobutyric acid (GABA) is synthesized from glutamate by glutamic acid decarboxylase (GAD), which requires pyridoxal phosphate (vitamin B6) as a cofactor. GABA is metabolized by GABA-transaminase (GABA-T) to succinic semialdehyde. Vigabatrin irreversibly inhibits GABA-T, increasing GABA levels.
GABA mediates roughly 40% of all inhibitory synaptic transmission in the mammalian brain.
GABA-A Receptors
GABA-A receptors are pentameric ligand-gated chloride channels, most commonly composed of 2alpha, 2beta, and 1gamma subunits. Chloride influx hyperpolarizes the neuron. The receptor contains multiple allosteric binding sites:
- Benzodiazepine site (alpha/gamma interface) -- diazepam, lorazepam increase chloride channel opening frequency
- Barbiturate site -- phenobarbital increases channel opening duration; at high doses, directly activates the channel
- Neurosteroid site -- allopregnanolone (brexanolone) enhances GABA-A function
- GABA binding site -- muscimol is a direct agonist; bicuculline is a competitive antagonist
- Picrotoxin site -- blocks the channel pore (convulsant)
Subunit composition determines pharmacology. Alpha-1 subunits mediate sedation; alpha-2/3 mediate anxiolysis. This has driven development of subtype-selective agents.
GABA-B Receptors
GABA-B receptors are Gi-coupled GPCRs that reduce calcium influx presynaptically and activate potassium channels postsynaptically. Baclofen is the primary GABA-B agonist, used for spasticity. GABA-B activation produces muscle relaxation and analgesia.
Key Drug Classes
- Benzodiazepines -- anxiolytics, hypnotics, anticonvulsants, muscle relaxants; reversed by flumazenil
- Z-drugs -- zolpidem, zaleplon preferentially bind alpha-1 GABA-A (sedation with less anxiolysis)
- Barbiturates -- phenobarbital for seizures; narrow therapeutic index
- Gabapentinoids -- gabapentin, pregabalin do not bind GABA receptors despite the name; they block alpha-2-delta calcium channel subunits
- Vigabatrin -- irreversible GABA-T inhibitor for refractory epilepsy
Key Takeaways
- GABA-A is a chloride channel with multiple allosteric drug-binding sites
- Benzodiazepines increase channel opening frequency; barbiturates increase duration
- GABA-B is a metabotropic receptor targeted by baclofen for spasticity
- Gabapentin and pregabalin are not true GABAergic drugs despite their names