GABA reuptake inhibitor

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A GABA reuptake inhibitor (GRI) is a type of drug which acts as a reuptake inhibitor for the neurotransmitter gamma-Aminobutyric acid (GABA) by blocking the action of the gamma-Aminobutyric acid transporters (GATs). This in turn leads to increased extracellular concentrations of GABA and therefore an increase in GABAergic neurotransmission.^[1] Gamma-aminobutyric acid (GABA) is an amino acid that functions as the predominant inhibitory neurotransmitter within the central nervous system, playing a crucial role in modulating neuronal activity in both the brain and spinal cord.^[2] While GABA predominantly exerts inhibitory actions in the adult brain, it has an excitatory role during developmental stages.^[3] When the neuron receives the action potential, GABA is released from the pre-synaptic cell to the synaptic cleft. After the action potential transmission, GABA is detected on the dendritic side, where specific receptors collectively contribute to the inhibitory outcome by facilitating GABA transmitter uptake. Facilitated by specific enzymes, GABA binds to post-synaptic receptors, with GABAergic neurons playing a key role in system regulation.^[4] The inhibitory effects of GABA diminish when presynaptic neurons reabsorb it from the synaptic cleft for recycling by GABA transporters (GATs).^[5] The reuptake mechanism is crucial for maintaining neurotransmitter levels and synaptic functioning.^[6] Gamma-aminobutyric acid Reuptake Inhibitors (GRIs) hinder the functioning of GATs, preventing GABA reabsorption in the pre-synaptic cell. This results in increased GABA levels in the extracellular environment, leading to elevated GABA-mediated synaptic activity in the brain.^[7][8]

Gamma-aminobutyric acid (GABA), the brain's main inhibitory neurotransmitter, plays a crucial role in regulating neuronal activity by dampening down neuron firing. Disruptions in GABAergic neurotransmission, such as reduced synthesis, reuptake dysfunction, or receptor abnormalities, can lead to various pathologies in the central nervous system, including epilepsy, anxiety disorders, Parkinson's disease, and sleep disorders. ^[9][10][11] The inhibitory neurotransmitter GABA plays a complex role in modulating anxiety and stress, regulating sleep, circadian rhythms, mood, cognition, and perception. Low GABA levels are associated with emotional and behavioral disruptions, including short-term and/or long-term stress, anxiety disorders, and sleep disorders.^[12]

GRIs may be used in the clinical treatment of seizures, convulsions, or epilepsy as anticonvulsants/antiepileptics, depression,^[13] anxiety disorders^[11] such as generalized anxiety disorder (GAD), social phobia (SP) also known as social anxiety disorder (SAD), and panic disorder (PD) as anxiolytics, insomnia as hypnotics, muscle tremors or spasms as muscle relaxants, and chronic pain as analgesics. They may also potentially be used as anesthetics in surgery.

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GRIs can induce a wide range of psychological and physiological effects, including:

Many of these properties are dependent on whether the GRI in question is capable of crossing the blood-brain-barrier (BBB). Those that do not will only produce peripheral effects.

GRIs such as CI-966 have been characterized as hallucinogens with effects analogous to those of the GABA_A receptor agonist muscimol (a constituent of Amanita muscaria (fly agaric) mushrooms) when administered at sufficient doses.^[14]

Tiagabine is another GRI that selectively inhibits the action of GABA reuptake and its mechanism of action is the same as selective serotonin reuptake inhibitor (SSRI).^[11] It is used as a treatment for partial seizures in adults and children over 12, and works by amplifying GABA's calming effects in the brain. This, however, comes with potential drawbacks. While generally well-tolerated, some users experience concentration issues, language difficulties, and even a higher risk of depression, hallucinations, and paranoia.^[15]

At very high doses characterized by overdose, a number of symptoms may come to prominence, including:

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• GABAergic
• Reuptake inhibitor

• Carlson NR, Birkett M (2017). Physiology of Behavior (12 ed.). Pearson. p. 103. ISBN 9780134320823.