What is the role of GABA (Gamma-Aminobutyric Acid) receptors?

From the Guidelines

GABA (Gamma-Aminobutyric Acid) receptors play a crucial role in the mammalian central nervous system as the primary inhibitory neurotransmitter system, and their dysfunction is implicated in various neurological and psychiatric disorders. The role of GABA receptors is to decrease neuronal excitability throughout the nervous system when activated by GABA, the main inhibitory neurotransmitter. There are two main types of GABA receptors:

• GABA-A receptors, which are ligand-gated ion channels that allow chloride ions to enter neurons, causing hyperpolarization and inhibition of action potentials;
• GABA-B receptors, which are G-protein coupled receptors that decrease calcium influx and increase potassium efflux, also resulting in neuronal inhibition. GABA receptors are crucial for maintaining the balance between neuronal excitation and inhibition in the brain. Many medications target GABA receptors, including benzodiazepines (like diazepam and alprazolam), which enhance the effect of GABA at GABA-A receptors, and baclofen, which activates GABA-B receptors 1. These medications are used to treat conditions like anxiety disorders, seizures, muscle spasms, and sleep disorders by increasing inhibitory neurotransmission in the brain. However, the use of benzodiazepines, which act on the GABA receptor complex, is associated with several adverse consequences, including cognitive impairment, reduced mobility, and addiction, and current consensus guidelines advise their use solely on a short-term basis 1. Additionally, other medications like gabapentin and pregabalin, which bind to the α2-δ subunit of voltage-gated calcium channels and inhibit the release of glutamate, norepinephrine, and substance P, are also used to treat neuropathic pain and other conditions 1. Overall, GABA receptors play a vital role in maintaining the balance of the nervous system, and their modulation by various medications can have significant therapeutic effects. The most recent and highest quality study 1 emphasizes the importance of using benzodiazepines, which target GABA receptors, with caution and only on a short-term basis due to their potential adverse consequences. Key points to consider when managing conditions related to GABA receptors include:
• The use of benzodiazepines should be limited to short-term treatment due to their potential for addiction and other adverse effects 1
• Other medications, such as gabapentin and pregabalin, may be effective alternatives for treating certain conditions, such as neuropathic pain 1
• The balance between neuronal excitation and inhibition is crucial for maintaining proper nervous system function, and dysfunction in GABA signaling can lead to various neurological and psychiatric disorders.

From the Research

Role of GABA Receptors

The role of GABA (Gamma-Aminobutyric Acid) receptors is multifaceted, playing a key part in the regulation of neuronal transmission throughout the brain, affecting numerous physiological and psychological processes 2.

Functions of GABA Receptors

• GABA receptors are involved in the development of numerous neuropsychiatric disorders, as changes in GABA levels provoke disbalance between excitatory and inhibitory signals 2.
• GABA exerts its effects via ionotropic (GABAA) and metabotropic (GABAB) receptors, which are targeted by many clinically important drugs used in the treatment of anxiety disorder, epilepsy, insomnia, spasticity, aggressive behaviour, and other pathophysiological conditions and diseases 2.
• GABAA receptors mediate fast synaptic inhibitory neurotransmission throughout the central nervous system and have been implicated in physiologically modulating anxiety and depression levels 3.
• GABA is also considered to be a multifunctional molecule that has different situational functions in the central nervous system, the peripheral nervous system, and in some nonneuronal tissues 4.

Subtypes of GABA Receptors

• The alpha2- and/or alpha3-containing GABA(A) receptors play a role in anxiety, whereas the alpha1 subtype is involved in sedation 5.
• Specific GABA(A) receptor subtypes in distinct neuronal circuits mediate benzodiazepine-induced behavioural responses, such as sedative, amnesic, anticonvulsant, anxiolytic-like, myorelaxant, motor-impairing, and ethanol-potentiating effects 6.

Therapeutic Applications

• Drugs that modulate GABAA receptor complex, such as benzodiazepines, barbiturates, neuroactive steroids, intravenous and inhalational anesthetics, and ethanol, are widely used in the treatment of various pathophysiological conditions and diseases 2.
• There is a growing interest in the development and application of subtype-selective drugs that will achieve specific therapeutic benefits without undesirable side effects, such as non-sedating anxiolytics 5.