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.
Gamma-aminobutyric acid (GABA) is an amino acid that serves as the primary inhibitory neurotransmitter in the brain and a major inhibitory neurotransmitter in the spinal cord. It exerts its primary function in the synapse between neurons by binding to post-synaptic GABA receptors which modulate ion channels, hyperpolarizing the cell and inhibiting the transmission of an action potential. The clinical significance of GABA cannot be underestimated. Disorder in GABA signaling is implicated in a multitude of neurologic and psychiatric conditions. Modulation of GABA signaling is the basis of many pharmacologic treatments in neurology, psychiatry, and anesthesia.[rx][rx][rx]
Functions of Gamma-aminobutyric Acid
Because GABA is the fundamental neurotransmitter for inhibiting neuronal firing, its function is determined by the neural circuit that it is inhibiting. It is involved in complex circuits throughout the central nervous system. For example, GABA is released by striatal neurons in both the direct and indirect pathways projecting to the globus pallidus, which in turn extends GABA neurons to other brain areas, inhibiting unwanted motor signals. Another example is that GABA signaling in the medulla is involved in the maintenance of respiratory rate. Increased GABA signaling reduces the respiratory rate. A third example is found in the spinal cord, where GABA serves in the inhibitory interneurons. These neurons help to integrate excitatory proprioceptive signals, allowing for the spinal cord to integrate sensory information and create smooth movements.[rx][rx][rx]
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.[rx]
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 GABA. [rx]
- 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 a positive charge. Typically, chloride will flow into the intracellular space. The addition of a 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. [rx]
- GABA receptor is a G-couple protein receptor. GABA 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 the presynaptic release of other neurotransmitters. GABA locations include the thalamic pathways and cerebral cortex.[rx]
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 play 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. [rx],[rx]
Pathophysiology of Gamma-aminobutyric Acid
GABA is involved in several disease states
- Pyridoxine deficiency is a rare disease in which the vitamin is not available for the synthesis of GABA. It usually presents as frequent seizures during infancy that are resistant to treatment with anticonvulsants but responds very well to vitamin supplementation.
- The clinical features of hepatic encephalopathy are thought to be due to elevated ammonia levels binding to the GABA-A/GABA complex and increasing chloride ion permeability.
- The symptoms of Huntington disease are partially caused by a lack of GABA in the striatal projections to the globus pallidus.
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. [rx]
- 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 a benzodiazepine can be fatal due to respiratory depression, especially if concomitant use with alcohol and opioids. Flumazenil is the reversal agent for benzodiazepines. [rx]
- GABA receptor agonists – Baclofen, sodium oxybate (GHB), propofol. GABA 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 the induction and maintenance of general anesthesia. Adverse effects include hypotension, apnea, and involuntary body movements. [rx],[rx],[rx]
- 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 pain, numbness, tingling, or weakness. সহজ বাংলা: স্নায়ুর ক্ষতি/সমস্যা।" data-rx-term="neuropathy" data-rx-definition="Neuropathy means nerve damage or irritation causing pain, numbness, tingling, or weakness. সহজ বাংলা: স্নায়ুর ক্ষতি/সমস্যা।">neuropathy, and postherpetic neuralgia. Gabapentin’s approved uses include postherpetic neuralgia and seizures. Off-label uses include diabetic pain, numbness, tingling, or weakness. সহজ বাংলা: স্নায়ুর ক্ষতি/সমস্যা।" data-rx-term="neuropathy" data-rx-definition="Neuropathy means nerve damage or irritation causing pain, numbness, tingling, or weakness. সহজ বাংলা: স্নায়ুর ক্ষতি/সমস্যা।">neuropathy and fibromyalgia. [rx]
GABA Antagonist
References
