GABA and Benzodiazepines in the Nervous System

GABA function?

GABA functions as an inhibitory neurotransmitter.

What effect does GABA have on neuron membrane potential?

GABA causes hyperpolarization.

What does hyperpolarization do to the membrane potential?

It makes the membrane potential more negative.

How does hyperpolarization affect the likelihood of firing an action potential?

It makes the neuron less likely to fire an action potential.

GABAa receptor

The GABAa receptor is a ligand-gated ion channel (ionotropic).

Ions permeated by GABAa receptors

GABAa receptors are selectively permeable to Cl- ions.

Location of GABAa receptors

GABAa receptors are primarily located postsynaptically.

GABAb receptor

The GABAb receptor is a G protein-coupled receptor (metabotropic).

Mechanism of GABAb receptors

GABAb receptors open potassium channels, reducing postsynaptic excitability.

Structure of GABAa receptors

GABAa receptors are pentamers made up of different subunits, typically two α, two β, and one γ.

Benzodiazepines binding site

Benzodiazepines bind at the α/γ interface of GABAa receptors.

Role of α1 subunits in GABAa receptors

α1 subunits are associated with sedation, addiction, anterograde amnesia, and anticonvulsant activity.

Role of α2 subunits in GABAa receptors

α2 subunits are associated with anxiolysis, anti-hyperalgesia, anti-depression, and myorelaxation.

Role of α3 subunits in GABAa receptors

α3 subunits are associated with sensorimotor gating, decreased thalamic oscillations, and myorelaxation.

Role of α5 subunits in GABAa receptors

α5 subunits are associated with sensorimotor gating, cognitive impairment, and myorelaxation.

Mechanism of action of benzodiazepines

Benzodiazepines are positive allosteric modulators that enhance the affinity of GABAa receptors for GABA.

GABAa receptor subunits sensitive to benzodiazepines

α1, α2, α3, and α5 subunits are sensitive to benzodiazepines.

Fast-acting long-lasting benzodiazepine

Diazepam.

Clinical uses of diazepam

Diazepam is used to treat muscle spasms, convulsions, anxiety, and symptomatic relief of alcohol withdrawal.

Fast-acting short-lived benzodiazepine

Lorazepam.

Clinical uses of lorazepam

Lorazepam is used for short-term relief of anxiety symptoms, anxiety-associated insomnia, anesthesia premedication, and convulsions.

Fast-acting ultra-short-lived benzodiazepine

Midazolam.

Clinical uses of midazolam

Midazolam is used for convulsions, sedation, and as an adjunct to antipsychotics in palliative care.

Fast-acting long-lived benzodiazepine

Clonazepam.

Clinical uses of clonazepam

Clonazepam is used for a broad spectrum of epilepsy and short-term management of panic disorders.

Short-term side effects of benzodiazepines

Short-term side effects include drowsiness, confusion, amnesia, ataxia, muscle weakness, and potentiation of sedative effects of other CNS depressants.