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Inhibits GABA and Glycine release
Convulsant |
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Tiagabine- is competitive inhibitor of the GABA transporter in neurons and glia (selective for GAT-1)
Increases both synaptic and extrasynaptic GABA concentrations, non-specific agonism both ionotropic and metabotropic GABA receptors
90% bioavailability, highly protein bound, metabolized by CYP3A4
Adverse Effects
confusion, sedation, amnesia, ataxia
Can potentiate other GABAA receptor modulators (i.e. alcohol, benzodiazepines, barbiturates) |
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γ-Vinyl GABA (vigabatrin)- is “suicide inhibitor” of GABA-transaminase (GABA-T). Blocks the conversion of GABA to succinic semialdehyde, leading to GABA concentrations synaptic release
Used in treatment of epilepsy. Being investigated for treatment of drug addiction, panic disorder, obsessive-compulsive disorder
Adverse Effects
Drowsiness, confusion, headache, bilateral visual field defects (from accumulation of drug in the retina) |
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GABA Receptor Agonist
Muscimol- bind directly to and activates GABAA. Muscimol was first derived from the the hallucinogenic Amanita muscaria mushroom. Full agonist at several GABAA subtypes primarily used as a research tool. |
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Bicuculline* and gabazine (competitive antagonist)
Benzodiazepines (BZPs)
Modulators of the GABAA receptor at allosteric binding sites to enhance GABAergic neurotransmission
BZPs have sedative, hypnotic, muscle relaxant, amnestic, and anxiolytic effects
High affinity, high selectivity at a single site on GABAA receptors, highly plasma bound (albumin)
BZPs act as positive allosteric modulators by enhancing GABAA receptor channel gating in the presence of GABA
BZPs increase frequency of channel openings in the presence of low GABA concentrations; when GABA concentrations are high, BZPs slow receptor deactivation both actions lead to net of Cl- influx
BZPs Do NOT activate Native GABAA receptors in the absence of GABA, but do activate certain mutant and enhance maximal activation of partial agonists indicating they are weak positive allosteric agonist
For GABA dose response curves, BZPs shift the dose response curve to the left potency
Margin of safety when BZPs are co-administered with alcohols or other sedative hypnotics |
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Barbiturates (BBTs)
Also a modulator of the GABAA receptor at allosteric binding sites to enhance GABAergic neurotransmission
Large group of drugs used for control of epilepsy, as general anesthetic induction, and control of intracranial hypertension… causes sedation, loss of consciousness, amnesia
GABAergic transmission at motor neurons of the spinal cord suppresses reflexes and relaxes muscles
Anesthetic BBTs (thiopental, pentobarbital and methohexital) act as both agonists at GABAA receptors and enhancers of GABAA responses
Anticonvulsant BBTs (phenobarbital) produce less agonism on native GABAA receptors
BBTs bind to specific site on GABAA receptors and not to the GABAA binding site
The major action of BBTs is to enhance the efficacy GABA by increasing the time that the Cl- channel stays open, permitting more influx of Cl- ions for each activated channel.
This leads to greater degree of hyperpolarization and less excitability.
BBTs GABA-enhancing ability is greater than that of BZPs
Overdoses of BZPs are deeply sedating but rarely dangerous, however BBTs overdose may induce profound hypnosis, or coma, respiratory depression and death |
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Baclofen is the only compound used in clinically that targets GABAB receptor
Primarily used for treatment of spasticity associated with motor neuron disease (multiple sclerosis) or spinal cord injury
Severe spasticity may be treated with intrathecal Baclofen
Baclofen stimulates downstream 2nd messenger to act on Ca2+ and K+ channels
May also modulate pain and cognition and being investigated for drug addiction.
Adverse Effect
Baclofen can cause sedation, somnolence(drowsiness), ataxia
Overdose produce blurry vision, hypotension, cardiac and respiratory depression, coma
Withdraw of Baclofen (especially intrathecal) can cause hyperspasticity, rhabdomyolsis (skeletal muscle breakdown), pruritus (itchy skin), delirium, fever, multi-organ failure, coagulation abnormalities, shock, and death |
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