CNS Pharmacology of GABA Receptors

For the receptor to activate, two molecules of GABA must bind to the interface between the $\alpha$ and $\beta$ subunits. Once activated, the channel allows an influx of chloride ions ($\text{Cl}^{-}$) into the neuron.

Hyperpolarization and IPSPs

Because chloride ions carry a negative charge, their influx makes the interior of the neuron more negative relative to the outside. This process is known as neuronal membrane hyperpolarization.

Hyperpolarization moves the membrane potential further away from the threshold required to fire an action potential, thereby reducing the likelihood of neuronal firing. This electrical response is referred to as an inhibitory postsynaptic current (IPSC).

Clinical Note: A reduction in GABA signaling (reduced IPSPs) can lead to increased neuronal excitability, manifesting as anxiety or seizures. Conversely, excessive GABA signaling can lead to sedation, motor incoordination, and even respiratory depression.

Pharmacological Modulation of $\text{GABA}_{\text{A}}$

The $\text{GABA}_{\text{A}}$ receptor is unique because it possesses several allosteric modulatory sites. These are locations on the receptor, distinct from the primary GABA binding site, where drugs can bind to enhance or inhibit the receptor's response.

Benzodiazepines

Benzodiazepines bind to a specific allosteric site located between the $\alpha$ and $\gamma$ subunits. They act as positive allosteric modulators, meaning they do not activate the receptor on their own, but they make the receptor more sensitive to GABA. Specifically, benzodiazepines increase the frequency of chloride channel opening.

Barbiturates

Barbiturates bind to a different site, adjacent to the $\alpha$ and $\beta$ subunits. Their mechanism of action is more potent and potentially more dangerous than benzodiazepines. They increase the duration of the chloride channel opening. Furthermore, at high doses, barbiturates can exert inhibitory effects even in the absence of GABA.

Ethanol (Alcohol)

Ethanol also interacts with the $\text{GABA}_{\text{A}}$ receptor complex. It binds to the receptor to enhance the influx of chloride ions, contributing to the sedative and motor-impairing effects of alcohol consumption.

Summary of Modulators

The $\text{GABA}_{\text{A}}$ receptor is a major target for various substances. In addition to the drugs mentioned above, the receptor also contains binding sites for steroids and inhalational anesthetics.

Exam Tip: Frequency vs. Duration A common way to distinguish these drugs on exams is by their effect on the chloride channel:

• Benzodiazepines $\rightarrow$ Increase Frequency of opening.
• Barbiturates $\rightarrow$ Increase Duration of opening.