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Gamma-aminobutyric acid (GABA) acts as the principal inhibitory neurotransmitter in the central nervous system (CNS). Although researchers discovered GABA in biological tissues in 1910, its neurological role in mammals remained unknown until the late 1950s.[1] Cortical neuron studies completed in the late 1960s concluded that GABA was unequivocally inhibitory. Many more follow-up studies were completed to elucidate the mechanisms of GABA-induced inhibition and its role in GABA-related pathologies, including anxiety disorders, alcohol use disorder, epilepsy, spastic diseases, and idiopathic hypersomnia.[2] The action of most anxiolytic drugs, antiepileptic drugs, and anesthetic drugs serve as GABA agonists.[3][4] Some GABA antagonists are useful as antidotes against GABA agonist overdoses.[5]

Alcohol use. Alcohol, or more specifically, ethanol, is a CNS depressant that works by potentiating the GABA-A receptor, inhibiting glutamate-binding NMDA receptors, and inhibiting VDCCs.[20][24] The euphoric effects of ethanol consumption are associated with the modification of GABA-A receptors in the mesolimbic dopamine reward system.  In patients with chronic ethanol consumption, the GABA-A mRNA and amount of GABA-A receptor expression changes such that they become less sensitive to GABA and its allosteric modulators, signaling a new, elevated GABA homeostasis. Thus, these patients are more likely to experience dependency, tolerance, and symptoms of alcohol withdrawal (anxiety, seizures, delirium, tachycardia) secondary to deficient GABA levels in the new GABA homeostasis. Fetal alcohol syndrome. The pathophysiology in fetal alcohol syndrome is mediated by ethanol binding to the GABA-A and NMDA receptors in the developing CNS.[24] Although the mechanism is not well-understood, current thought is that ethanol starts a pro-apoptotic cascade in millions of neurons by activating GABA-A receptors and VDCCs, causing excitotoxicity in these neurons. Anxiety disorders. Anxiety disorders such as panic disorder, post-traumatic stress disorder, and generalized anxiety disorder are associated with decreased levels of GABA.[25][26] GABA is inhibitory toward corticotropin-releasing hormone (CRF) and vasopressin, which are neuropeptides released from the paraventricular nucleus of the hypothalamus to stimulate the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is associated with stress, so chronic overactivity of the HPA axis contributed in part by GABA is associated with pathologic stress, depression, and anxiety. Patients with disorders of anxiety have reduced response to benzodiazepines and downregulated GABA release. The amygdala, a brain site for the creation and storage of memories associated with fear, is also associated with anxiety disorders as patients with anxiety often have amygdala overactivation. There are many GABAnergic neurons in the amygdala compared to other brain regions, and their role is thought to involve inducing long-term potentiation to regulate fear generalization.

Anxiety disorders. Anxiety disorders such as panic disorder, post-traumatic stress disorder, and generalized anxiety disorder are associated with decreased levels of GABA.[25][26] GABA is inhibitory toward corticotropin-releasing hormone (CRF) and vasopressin, which are neuropeptides released from the paraventricular nucleus of the hypothalamus to stimulate the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is associated with stress, so chronic overactivity of the HPA axis contributed in part by GABA is associated with pathologic stress, depression, and anxiety. Patients with disorders of anxiety have reduced response to benzodiazepines and downregulated GABA release. The amygdala, a brain site for the creation and storage of memories associated with fear, is also associated with anxiety disorders as patients with anxiety often have amygdala overactivation. There are many GABAnergic neurons in the amygdala compared to other brain regions, and their role is thought to involve inducing long-term potentiation to regulate fear generalization. Depression. Although depression is primarily associated with alterations in dopamine, norepinephrine, and serotonin, GABA signaling deficits also play a role in depression.[27] A [11C]-flumazenil PET study of patients with major depression found a reduced number of GABAnergic neurons in the orbitofrontal cortex, plasma GABA titers, and the amount of cortical GABA-A receptor. Epileptic disorders and tremors. Epileptic seizures are thought to be paroxysmal hypersynchronous electrical discharges due to overexcitation of neurons in the brain.[8] Tremors are contributed in part by the death of GABAnergic neurons in the cerebellum.[28] These syndromes often result from an imbalance in the glutamate-GABA equilibrium due to either too much excitation or too little inhibition. Several diseases and injuries to the brain, including stroke, Parkinson’s disease, spastic cerebral palsy, and traumatic brain injuries have epileptic or tremorous activity secondary to damage to inhibitory interneurons.[29][30]

Epileptic disorders and tremors. Epileptic seizures are thought to be paroxysmal hypersynchronous electrical discharges due to overexcitation of neurons in the brain.[8] Tremors are contributed in part by the death of GABAnergic neurons in the cerebellum.[28] These syndromes often result from an imbalance in the glutamate-GABA equilibrium due to either too much excitation or too little inhibition. Several diseases and injuries to the brain, including stroke, Parkinson’s disease, spastic cerebral palsy, and traumatic brain injuries have epileptic or tremorous activity secondary to damage to inhibitory interneurons.[29][30] Huntington's disease. The protein involved in Huntington disease, Huntingtin, inhibits the transcription and transport of GABA-A receptors and KCC2, causes neuroinflammation that weakens the inhibitory response and disruption of astrocytic glutamate transporters.[31] This leads to decreased inhibition that may be associated with Huntington chorea. Diseases involving excessive GABA. Excessive GABA release can also be pathologic and manifests as idiopathic hypersomnia (IH), a condition that manifests as daytime sleepiness with excessive, unrefreshing sleep.[32] Although the etiology of idiopathic hypersomnia is poorly understood, the thinking is that there is hyperactivity of GABA-A receptors due to excessive GABA in the synapse and cerebrospinal fluid. Semialdehyde succinate dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder in which the enzyme involved in the degradation of GABA, semialdehyde succinate dehydrogenase, becomes defective.[33] Patients with SSADH have a buildup of gamma-hydroxybutyrate (GHB), a metabolic product derived from the reduction of excessive semialdehyde succinate. GABA transaminase (GABA-T) deficiency is an extremely rare defect of the first enzyme in GABA degradation that manifests as hyperreflexia and refractory seizures.[34]