Introduction

Gamma-aminobutyric acid (GABA) is an amino acid that functions as the primary inhibitory neurotransmitter for the central nervous system (CNS). It functions to reduce neuronal excitability by inhibiting nerve transmission. GABAergic neurons are located when the hippocampus, thalamus, basal ganglia, hypothalamus, and brainstem. The balance between inhibitory neuronal transmission via GABA and excitatory neuronal transmission via glutamate is essential for proper cell membrane stability and neurologic function.

Function

Synthesis

• GABA is formed from glutamate via the addition of glutamate decarboxylase and vitamin B6. GABA can then be used to form succinate, which is involved in the citric acid cycle. Once GABA is formed, is it released into the post-synaptic terminals of neurons.
• Although glutamate is a precursor for GABA, their roles are opposite in the nervous system. Glutamate is considered an excitatory neurotransmitter, while GABA is an inhibitory neurotransmitter. The imbalance of glutamate and GABA can play a role in various pathologies, as discussed in Clinical Significance.[1]

Receptors

• GABA receptors are receptors that respond when GABA is released into the post-synaptic nerve terminal. They are considered the chief inhibitory receptors for the central nervous system. GABA receptors are subdivided into GABAa and GABAb. [2]
• GABAa is classified as a ligand-gated ion channel/inotropic receptor. GABAa is considered in fast synaptic inhibition. Upon the receptor binding to GABA, an ion pore opens to allow chloride to move across the cell membrane. Chloride is a negatively charged ion and will follow into the area of positive charge. Typically, chloride will flow into the intracellular space. The addition of negative charge will decrease the resting potential of the cell, thus causing an inhibitory effect. GABAa receptors are located throughout the central nervous system. However, they have high concentrations in the limbic system and the retina. [2]
• GABAb receptor is a G-couple protein receptor. GABAb receptors are considered slow synaptic inhibitors. After GABA has bound to the receptor, potassium conductance is increased. Adenylyl cyclase is activated, which prevents calcium entry thus inhibits presynaptic release of other neurotransmitters. GABAb locations include the thalamic pathways and cerebral cortex.[3]

Brain Development 

• Within the adult central nervous system, GABA is the primary inhibitory neurotransmitter. However, during embryonic development, GABA acts as an excitatory neurotransmitter. GABA is thought to be the first neurotransmitter active within the developing brain and plays a role in the proliferation of neuronal progenitor cells. High levels of GABA in ventricular areas increased proliferation and neural progenitor cell size; however, in the subventricular zone, GABA decreased proliferation. [4],[5]

Clinical Significance

Various diseases have been associated with low levels of GABA. Many psychiatric illnesses have been linked to low concentrations of GABA. Generalized anxiety is one example. As GABA is an inhibitory neurotransmitter, decreased concentration of it would produce a feeling of anxiousness. It has also been associated with schizophrenia, autism spectrum disorder, and major depressive disorder. It is important to note that although GABA concentrations may be altered in these psychiatric diseases, treatment using GABAa receptor agonists are not first-line therapy, due to high addiction potential and potentially fatal adverse effect. Valproic acid, a GABA analog, can be used for mood instability due to the enhancement of GABA concentrations. [1],[6]

Seizures and epilepsy are associated with low levels of GABA. With decreased levels of inhibition in the cerebral cortex, cells become depolarized, leading to seizure activity. GABA agonists, such as Valproic acid, are used for the treatment of seizures. Abrupt withdrawal from medications such as benzodiazepines, a GABAa positive allosteric modulator, can provoke seizures. Also, GABA antagonists are pro-convulsant. [7]

Inherited disorders of GABA metabolism are rare and therefore require an increase in clinical suspension. The most common diseases are GABA-transaminase deficiency, succinic semialdehyde dehydrogenase deficiency (SSADH), and homocarnosinosis. SSADH is the most common of neurotransmitter deficiencies. It presents with vague phenotype, varying neurological manifestations, and psychiatric illness. GABA is unable to be converted to succinic acid, and gamma-hydroxybutyrate (GHB) accumulates. Elevated concentrations of GABA and GHB are found within serum and urine. Diagnosis can be made with urinary excretion of GABA and increased signaling in the globus pallidus on MRI. Characteristics include expressive language impairment, hypotonia, and seizures. The most common neuropsychiatric problem is sleep disturbance; other issues include inattention, hyperactivity, and obsessive-compulsive disorder (OCD). There is currently no standard treatment for SSADH deficiency. [8]

GABA-transaminase deficiency and homocarnosinosis are much rarer. GABA-transaminase deficiency is an autosomal recessive disorder. Patients may have seizures presenting in the neonatal period; other manifestations include hypotonia, hyperreflexia, severely delayed psychomotor development, and a high-pitched cry. High concentrations of GABA are found in serum and cerebrospinal fluid (CSF). Cerebrospinal fluid is needed for diagnosis. Homocarnosinosis has only been reported in one family. Characteristics include progressive spastic diplegia, intellectual disability, and retinitis pigmentosa. [8]

Other Issues

Pharmacology

GABA Agonist

Drugs that increase the amount of GABA are commonly used as anticonvulsants, sedatives, and anxiolytics. Due to the increase in GABA, CNS depression is a common adverse effect. Some GABA agonist has addiction potential, and use should be monitored closely. [9]

• GABAa receptor agonists: Alcohol (ethanol), barbiturates, and benzodiazepine. Barbiturates include phenobarbital and sodium thiopental. Barbiturates are less frequently used due to the high addiction potential and lack of an antidote. Benzodiazepines have mainly replaced them. Benzodiazepines can treat anxiety, agitation, seizures, and muscle spasms. Only short-term use of benzodiazepine is encouraged. An overdose of benzodiazepines can be fatal due to respiratory depression, especially if concomitant use with alcohol and opioids. Flumazenil is the reversal agent for benzodiazepines. [9]
• GABAb receptor agonists: Baclofen, sodium oxybate (GHB), propofol. GABAb agonists increase CNS depression. Baclofen is typically used as a muscle relaxant to treat spasticity. GHB is approved for the treatment of narcolepsy. Severe CNS depression is common is GHB. Significant respiratory depression and obtundation are commonly seen. Propofol is used for induction and maintenance of general anesthesia. Adverse effects include hypotension, apnea, and involuntary body movements. [9][10][11]
• GABA analogs: Valproic acid, pregabalin, gabapentin. GABA analogs are used as anticonvulsants, sedatives, and anxiolytics. As with other medications that increase GABA, CNS depression is common in this class of drugs. Valproate is prescribed for the treatment of seizures and mood instability. Pregabalin is used for fibromyalgia, diabetic neuropathy, and postherpetic neuralgia. Gabapentin’s approved uses include postherpetic neuralgia and seizures. Off-label uses include diabetic neuropathy and fibromyalgia. [9]

GABA Antagonist

Drugs that bind to but do not increase the amount of GABA are considered antagonists. Examples include picrotoxin or bicuculline methiodide. Both are mainly used for research. GABA antagonists are pro-convulsant and stimulants. [7],[12]

Enhancing Healthcare Team Outcomes

The healthcare team, including physicians, physician assistants, nurse practitioners, nurses, and pharmacists must work together to monitor the usage of GABA receptor agonists. The time should recall that low levels of GABA are associated with seizures and precautions should be taken.