GABA reuptake inhibitor
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A GABA reuptake inhibitor (GRI) is a type of
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]
Indications
GRIs may be used in the
Effects
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GRIs can induce a wide range of
- general and subjective alteration in consciousness
- dizziness
- blurry vision
- diplopia or double vision
- eye movements
- amblyopia or "lazy eye"
- 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
- 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
- muscle tremors and spasms
- paresthesia or "pins and needles"
- analgesia
- respiratory depression
- breath
Many of these properties are dependent on whether the GRI in question is capable of crossing the
GRIs such as CI-966 have been characterized as hallucinogens with effects analogous to those of the GABAA 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
Overdose
At very high doses characterized by
- severe cognitive deficit to the point of acute retardation
- anterograde or retrograde amnesia
- drooling
- piloerectionor "goose bumps"
- agitation or restlessness
- flailing
- thrashing and screaming
- unintentional or accidental injury
- delirium
- hallucinations
- myoclonus
- dystonia
- paralysis
- stupor
- loss of consciousness
- seizures or convulsions
- status epilepticus
- coma and respiratory arrest or cessation of breathing
- brain damage
- death
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]
See also
References
- PMID 19043517.
- PMID 30020683, retrieved 2024-02-15
- PMID 30252380, retrieved 2024-02-15
- PMID 2847312.
- ^ Olsen RW, DeLorey TM (1999), "GABA Synthesis, Uptake and Release", Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition, Lippincott-Raven, retrieved 2024-02-15
- ^ Salters-Pedneault, K. (2023, June 13). How selective serotonin reuptake inhibitors (ssris) works. Verywell Mind.
- PMID 30255012.
- S2CID 224856466.
- PMID 37603262.
- PMID 35676483.
- ^ a b c Loughlin, K. R., Generali, J. A. (2006). The Guide to Off-label Prescription Drugs: New Uses for FDA-approved Prescription Drugs. United Kingdom: Free Press.
- PMID 33041752.
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- ^ Cavanna, A. E., Ali, F., Rickards, H. E., & McCorry, D. (2010). Behavioral and cognitive effects of anti-epileptic drugs. Discovery medicine, 9(45), 138–144.
- ^ PMID 7851497.
- PMID 10882845.
- Carlson NR, Birkett M (2017). Physiology of Behavior (12 ed.). Pearson. p. 103. ISBN 9780134320823.