GABA
General
- GABA is the main inhibitory neurotransmitter.
- A third of the synapses in the brain use GABA as their inhibitory neurotransmitter.
- GABA is most commonly found in local circuit interneurons, although cerebellar Purkinje cells provide an example of a GABAergic projection neuron.
- A highly flexible molecule and, thus, can exist in many low-energy conformations.
Synthesise
- Precursor for GABA synthesis is glucose, which is metabolized to glutamate by the tricarboxylic acid cycle enzymes (pyruvate and glutamine can also act as precursors).
- The enzyme glutamic acid decarboxylase (GAD), which is found almost exclusively in GABAergic neurons, catalyzes the conversion of glutamate to GABA.
- GAD requires a cofactor, pyridoxal phosphate, for activity. Because pyridoxal phosphate is derived from vitamin B6, a B6 deficiency can lead to diminished GABA synthesis.
- Once GABA is synthesized, it is transported into synaptic vesicles via a vesicular inhibitory amino acid transporter (VIATT).
Metabolism
- The mechanism of GABA removal is similar to that for glutamate: Both neurons and glia contain high-affinity transporters for GABA, termed GATs.
- Most GABA is eventually converted to succinate, which is metabolized further in the tricarboxylic acid cycle that mediates cellular ATP synthesis. The enzymes required for this degradation, GABA transaminase and succinic semialdehyde dehydrogenase, are mitochondrial enzymes.
GABA receptors
GABA A receptors
- Transmitter-gated Cl- channels → activation causes Cl- influx → membrane hyperpolarization
- Activated by steroids, barbiturates and benzodiazepines (BZ), Propofol
- BZs reach a plateau in CNS depression; barbiturates and alcohol do not
- Cross-tolerance occurs between BZs, barbiturates, and ethanol
BZ
- Potentiate GABA → inc. the frequency of Cl- channel opening
- Have no GABA mimetic activity
- Act through BZ receptors
- These receptors are part of the GABAA complex
- BZ1 mediates sedation
- Zolpidem and zaleplon
- BZ1 receptor agonist
- Less effect on cognitive function (BZ2-mediated)
- Not effective for chronic anxiety, seizure disorders, or muscle relaxation.
- Overdose reversed by flumazenil
- Used in sleep disorders
- Less tolerance and abuse liability (sleepwalking)
- BZ2 mediates antianxiety and impairment of cognitive functions
- Pharmacokinetics
- Liver metabolites are also active compounds, except for oxazepam, temazepam, and lorazepam
- Withdrawal
- Rebound insomnia
- Anxiety
- Seizures when BZs were used as antiepileptic or in high doses
- Commonly used Benzodiazepines
Drug | Dose | Onset | Duration | Comments |
Midazolam | 1–2 mg IV | Rapid | Short (the shortest) | 4 times more potent than diazepam; excellent anticonvulsant; always monitor patient |
Clorazepate | 15–60 mg/d, divided | Rapid | Long | ㅤ |
Diazepam | 2–10 mg BID-QID | Rapid | Long (the longest) | ㅤ |
Flurazepam | 30 mg | Rapid/ intermediate | Long | ㅤ |
Alprazolam | 0.25–0.5 mg TID | Intermediate | Intermediate | Antidepressant effects |
Chlordiazepoxide | 5–10 mg TID | Intermediate | Long | ㅤ |
Lorazepam | 1 mg TID | Intermediate | Intermediate | Not metabolized in liver |
Halazepam | 20–40 mg TID | Intermediate | Long | ㅤ |
Oxazepam | 10–15 mg TID | Intermediate/slow | Intermediate/ short | Not metabolized in liver |
Temazepam | 15–30 mg | Intermediate/slow | Intermediate | Not metabolized in liver |
Prazepam | 20–60 mg/d divided | Slow | Long | ㅤ |
- Reversal
- Flumazenil
- Nonspecific BZ receptor antagonist is used to reverse the CNS depression caused by BZs used in anesthesia or in BZ overdose.
- Can provoke seizures in chronic benzodiazepine users
- Flumazenil cannot reverse the CNS depression caused by barbiturates and alcohols
Barbiturates
- Prolong GABA activity → inc duration of Cl- channel opening
- Have GABA mimetic activity at high doses
- Do not act through BZ receptors
- Have their own binding sites on the GABAA complex
- Also inhibit complex I of electron transport chain
- Pharmacokinetics
- Liver metabolized, sometimes to active compounds
- General inducers of cytochrome P450s
- Withdrawal
- Anxiety
- Agitation
- Life-threatening seizures (delirium tremens with alcohol)
GABA B receptors
- Metabotropic (G-proteins coupled receptors)
- Seven transmembrane receptors that are coupled to G-proteins → activate second messenger systems and Ca2+ and K+ ion channels. → activation K+ efflux → membrane hyperpolarization
- In brain are inhibitory
- Activated By
GABA C receptors
- Transmitter-gated ion channels
- Cl- channel made up of a single type of protein subunit → causes hyperpolarization
- These receptors are not blocked by steroids, barbiturates or benzodiazepines.
Other drugs that can exert effect on GABA receptors
Tiagabine
- Inc. GABA by inhibiting re-uptake
Vigabatrin
- Irreversible GABA transaminase inhibitor
Gabapentin
- Primarily inhibits high-voltage activated Ca2+ channels → inhibit the release of excitatory neurotransmitters in the presynaptic area that participate in epileptogenesis.
- Although it has a structure similar to GABA, it does not bind to GABA receptors or influence the synthesis or uptake of GABA.
Levetiracetam
- May modulate GABA and glutamate release
Buspirone
- A nonbenzodiazepine anxiolytic.
- A partial 5HT1A receptor.
- It has no dependence effects and no symptoms of withdrawal
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