GABA reuptake inhibitor

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)

Main article: Reuptake inhibitor

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]

Indications

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.

Effects

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

• general and subjective alteration in consciousness
• dizziness
• blurry vision
• diplopia or double vision
• nystagmus or involuntary eye movements
• amblyopia or "lazy eye"
• tinnitus or "ear ringing"
• sedation
• drowsiness or somnolence
• narcolepsy
• tiredness or weakness
• fatigue or lethargy
• aches and pains
• headache
• nausea and vomiting
• gastrointestinal disturbances
• shakiness
• disorientation
• diminished awareness
• impaired attention
• focus and concentration
• decreased drive and motivation
• stuttering and slurring of speech
• confusion
• cognitive and memory impairment
• mood lift or drop
• depression
• anxiolysis
• disinhibition
• stress reduction
• euphoria or dysphoria
• irritability
• aggression
• anger or rage
• increased appetite and subsequent weight gain
• ataxia or impaired coordination and balance
• muscle relaxation
• trembling or muscle tremors and spasms
• paresthesia or "pins and needles"
• analgesia
• respiratory depression
• dyspnea or shortness of breath

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]

Overdose

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

• severe cognitive deficit to the point of acute retardation
• anterograde or retrograde amnesia
• drooling
• piloerection or "goose bumps"
• agitation or restlessness
• flailing
• thrashing and screaming
• unintentional or accidental injury
• delirium
• hallucinations
• myoclonus
• dystonia
• paralysis
• stupor
• faintness or loss of consciousness
• seizures or convulsions
• status epilepticus
• coma and respiratory arrest or cessation of breathing
• brain damage
• death

^{[citation needed]}

List of GRIs

• CI-966^[16]
• Deramciclane (EGIS-3886)
• Gabaculine
• Guvacine (C10149)
• Nipecotic acid
• NNC 05-2090
• NNC-711^[16]
• SKF-89976A^[16]
• SNAP-5114
• Tiagabine (Gabitril)^[16]
• Hyperforin^[17]
• Arecaidine

See also

• GABAergic
• Reuptake inhibitor