Introduction

Gamma-aminobutyric acid (GABA) is an amino acid that functions as the primary inhibitory neurotransmitter in the central nervous system (CNS). GABA is synthesized from the excitatory neurotransmitter glutamate and reduces neuronal excitability by causing neuronal hyperpolarization and decreasing neurotransmitter release. The activity of GABA is regulated by binding through 3 receptors—GABA-A, GABA-B, and GABA-C.

GABAergic neurons are located in the hippocampus, thalamus, basal ganglia, hypothalamus, and brainstem. Maintaining a balance between inhibitory neuronal transmission mediated by GABA and excitatory neuronal transmission mediated by glutamate is essential for maintaining cell membrane stability and proper neurological function.[1] Disruption of the balance between glutamate and GABA has a functional role in various pathologies, including traumatic brain injury, Alzheimer disease, epilepsy, schizophrenia, and autism.[1][2] The role of GABA receptors in analgesia is also being investigated.[3][4]

Function

Synthesis, Release, and Reuptake

GABA is synthesized from glutamate by the enzyme glutamic acid decarboxylase (GAD), which requires pyridoxal phosphate—a cofactor derived from pyridoxine (vitamin B6). Once formed, GABA is transported into vesicles by the vesicular inhibitory amino acid transporter. These vesicles are released into the postsynaptic terminals of neurons through calcium-dependent exocytosis.[5]

GABA transaminase can be further metabolized by GABA transaminase into succinic semialdehyde (SSA) and succinic acid, which enter the citric acid cycle to participate in energy production.[6] The transamination of GABA into SSA is coupled with the conversion of α-ketoglutarate to glutamate, which is subsequently taken up by the neuron for the synthesis of GABA.

Receptors 

GABA receptors are the primary inhibitory receptors in the CNS, and they are classified into 3 types—GABA-A, GABA-B, and GABA-C receptors.[7]

GABA-A receptors: GABA-A receptors are ligand-gated ion channel (ionotropic) heteropentamer receptors composed of a selection of 19 different subunits. These include 6 alpha subunits (α 1-6), 3 beta subunits (β 1-3), 3 gamma subunits (γ 1-3), 3 rho subunits (ρ 1-3), and 1 each of delta (δ), epsilon (ε), pi (π), and theta (θ) subunits. Although numerous combinations are possible with this selection, most GABA-A receptors exist as a combination of 2α and 2β subunits and either a γ- or δ-subunit.[8]

One of the more common combinations is γ2β2α1β2α1 arranged counterclockwise from the center subunit.[9] Different isoforms of the receptor exhibit different physiological and pharmacological properties. Additionally, certain isoforms may have restricted expression patterns based on their specific functions. The binding sites for GABA are located at the β-α interfaces within the receptor.[9][10]

GABA-A receptors are primarily involved in fast synaptic inhibition. When GABA binds to the receptor, an ion channel opens, thereby allowing chloride ions to move across the cell membrane. As chloride is negatively charged, this results in hyperpolarization, making the membrane potential more negative and less sensitive to depolarization. GABA-A receptors are located throughout the CNS, both at postsynaptic and extrasynaptic sites, with high concentrations in the limbic system and the retina.[7]

GABA-B receptors: GABA-B receptors are G-protein–coupled heterodimers composed of B1 (B1a and B1b) and B2 subunits. They function as slow synaptic inhibitors, exerting inhibitory effects through the second messenger system. The effect of GABA-B receptor activation depends on whether it occurs at the pre- or postsynaptic terminal. In the presynaptic terminal, GABA binding reduces adenylyl cyclase activity, leading to a decrease in cyclic adenosine monophosphate (cAMP) levels. This action inhibits neurotransmitter release.

Other effects include the inhibition of inward-rectifying calcium channels, further preventing neurotransmitter release. Postsynaptically, the inhibition of adenylyl cyclase decreases protein kinase A signaling and reduces the permeability of ion channels. Additionally, the stimulation of inward-rectifying potassium channels leads to further hyperpolarization.[11][12]

GABA-C receptors: GABA-C receptors are pentameric ligand-gated ion channels, similar to GABA-A receptors. They are unique in that they consist of only ρ subunits (ρ1, ρ2, and ρ3).[13] The role of GABA-C receptors is not fully understood and remains under investigation, although they appear to have an important role in retinal signal processing.[14][15]

Brain Development 

Although GABA functions as an inhibitory neurotransmitter in the adult brain, it acts differently during embryonic development. GABA functions as an excitatory neurotransmitter during the neurodevelopment of the fetus. GABA is believed to be the first neurotransmitter active in the developing brain and has a role in the proliferation of neuronal progenitor cells.[16] High levels of GABA in ventricular areas are associated with increased proliferation and larger neural progenitor cells. However, in the subventricular zone, GABA appears to decrease proliferation.[17][18]

Clinical Significance

GABA-A receptors play a crucial role in the modulation of seizures.[19] Chronic exposure to certain xenobiotics that stimulate GABA receptors, such as ethanol and benzodiazepines, can modulate GABA receptor expression and sensitivity. Overstimulation of GABA receptors leads to receptor downregulation and decreased neuronal sensitivity to GABA. When these substances are abruptly discontinued, there is a sudden reduction in the overall inhibitory signal, which can trigger seizures.[20]

In epilepsy, the dysfunction or loss of inhibitory interneurons in the cerebral cortex results in a loss of inhibition of excitatory neurons. This causes neurons to depolarize more easily, resulting in uncontrolled excitation and subsequent seizure activity.[21] Compounds such as picrotoxin and bicuculline, which are GABA antagonists, act as pro-convulsants.[8][22]

Various diseases, including many psychiatric illnesses, have been linked to low levels of GABA. Generalized anxiety is 1 such example. As an inhibitory neurotransmitter, decreased GABA levels can contribute to feelings of anxiousness. Reduced GABA levels have also been associated with schizophrenia, autism spectrum disorder, and major depressive disorder. Although GABA concentrations may be altered in these psychiatric conditions, treatment with GABA-A receptor agonists is not considered first-line therapy due to their high addiction potential and potentially fatal adverse effects.[2][23]

Inherited Disorders

Inherited disorders of GABA metabolism are rare. The most common conditions include GABA-transaminase deficiency, SSA dehydrogenase (SSADH) deficiency, and homocarnosinosis. Of these, SSADH deficiency is the most prevalent deficiency of a neurotransmitter. This condition presents clinically with a vague phenotype, a range of neurological manifestations, and psychiatric symptoms. The inability to convert GABA to succinic acid results in the accumulation of gamma-hydroxybutyrate (GHB). Elevated levels of both GABA and GHB can be detected in serum and urine.

Diagnosis can be confirmed through the urinary excretion of GABA and increased signaling in the globus pallidus on magnetic resonance imaging. Key characteristics include expressive language impairment, hypotonia, and seizures. The most common neuropsychiatric issue is sleep disturbance, with other concerns including inattention, hyperactivity, and obsessive-compulsive disorder. Currently, there is no standard treatment for SSADH deficiency.[24]

GABA-transaminase deficiency and homocarnosinosis are much rarer. GABA-transaminase deficiency is an autosomal recessive disorder. Patients may experience seizures that present in the neonatal period, with other manifestations including hypotonia, hyperreflexia, severely delayed psychomotor development, and a high-pitched cry. Elevated concentrations of GABA, homocarnosine, and β-alanine can be found in serum and cerebrospinal fluid.[25]

Homocarnosinosis has been reported in only 1 family. This disorder results from the accumulation of homocarnosine, a dipeptide composed of GABA and histidine.[26] Key characteristics of this condition include progressive spastic diplegia, intellectual disability, and retinitis pigmentosa.[24]

Poisoning from certain xenobiotics, such as isoniazid, rocket fuel (hydrazine), and the consumption of the false morel (Gyromitra esculenta) mushroom, which contains the hydrazine derivative gyrometrin, can lead to the depletion of GABA.[27][28] Specifically, hydrazine compounds deplete pyridoxine (vitamin B6) and inhibit the formation of pyridoxal phosphate, which in turn inhibits the activity of GAD. This disruption prevents the synthesis of GABA, leading to its eventual depletion and causing seizures that are refractory to benzodiazepines. Treatment involves the administration of pyridoxine.[27]

Other Issues

GABA Agonists

GABA agonists, such as commonly prescribed anticonvulsants, sedatives, and anxiolytics, can increase GABA levels, leading to CNS depression. Prolonged use of these GABA agonists can result in physiological dependence and, in some cases, addiction.[29]

GABA-A receptor agonists: GABA-A receptor agonists include alcohol (ethanol), barbiturates, and benzodiazepines.

• Barbiturates, such as phenobarbital and sodium thiopental, are used less frequently due to their higher risk of respiratory depression compared to benzodiazepines. However, barbiturates, especially phenobarbital, are increasingly utilized in the treatment of acute alcohol withdrawal.[30][31][32][33]
• Benzodiazepines, including lorazepam, diazepam, clonazepam, alprazolam, oxazepam, and chlordiazepoxide, were developed to minimize adverse effects associated with barbiturates, such as respiratory depression. Clinical indications for benzodiazepines include anxiety, agitation, seizures, and muscle spasms. Only short-term use is recommended. Although benzodiazepine overdose can cause significant sedation, respiratory depression rarely occurs when benzodiazepines are taken alone. However, the risk of respiratory depression increases significantly with co-ingestants such as alcohol or opioids. Flumazenil, a benzodiazepine antagonist, is used to reverse overdose in certain situations. However, flumazenil can induce iatrogenic seizures that may be refractory to subsequent benzodiazepine administration, particularly in patients with physiological dependence.[29]

GABA-B receptor agonists: GABA-B receptor agonists include baclofen, sodium oxybate (GHB), and propofol.

• Baclofen is a muscle relaxant commonly used to treat spasticity. This medication is available in oral formulations or can be administered via an implanted pump.
• GHB is approved for the treatment of narcolepsy. GHB is also increasingly used recreationally in the club scene, during "chemsex," and as a drug to facilitate sexual assault.[34][35][36][37] Severe CNS depression is common in individuals who have taken GHB. Significant respiratory depression and obtundation are frequently observed, and it is not uncommon for patients to require intubation.[38]
• Propofol is used for the induction and maintenance of general anesthesia, as well as for sedation in mechanically ventilated patients. Adverse effects include hypotension, apnea, and involuntary body movements.[29][39][40]

GABA analogs: GABA analogs, including valproic acid, pregabalin, gabapentin, and vigabatrin, are used as anticonvulsants, sedatives, and anxiolytics.

• Valproate is prescribed to treat seizures and mood instability. Although it is a GABA analog, the exact mechanism of action of valproate is not fully understood. Valproate is believed to exert its effects through multiple mechanisms, including modulation of sodium, calcium, and potassium channels, as well as GABAergic actions, such as the inhibition of GABA transaminase.[41]
• Pregabalin is used to treat fibromyalgia, diabetic neuropathy, and postherpetic neuralgia. Although it is a GABA analog, it does not act on GABA-mediated neurotransmission. Instead, it primarily inhibits voltage-gated calcium channels, reducing glutamate release.[41][42]
• Gabapentin is approved for the treatment of postherpetic neuralgia and seizures, with off-label uses, including the management of diabetic neuropathy and fibromyalgia.[29] Gabapentin functions similarly to pregabalin by inhibiting voltage-gated calcium channels.[41][42]

GABA Antagonists

GABA antagonists are drugs that inhibit the activation of the GABA receptor, typically by binding to sites other than the receptor's binding sites. Examples include picrotoxin and bicuculline methiodide, which are primarily used for research purposes. GABA antagonists are pro-convulsant and exhibit stimulant properties.[22][43]

Enhancing Healthcare Team Outcomes

GABA is a crucial inhibitory neurotransmitter in the human brain. Dysfunction in the GABA system can lead to various disease processes, resulting in an imbalance between the GABA and glutamate systems. These conditions may include psychiatric illnesses, dementia, drug dependence or addiction, and drug overdose or toxicity. Many of these conditions can be treated with medications, including GABA agonists.

The healthcare team, including primary care providers, nurses, and pharmacists, must possess the necessary knowledge to prescribe and administer these medications safely. Each healthcare team member is responsible for monitoring adverse drug effects and periodically reviewing the indications for these medications to minimize risks. Additionally, healthcare providers should be able to recognize signs and symptoms of toxicity, such as severe sedation or respiratory depression, to ensure prompt diagnosis and treatment.