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).

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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

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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

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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

Baclofen

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.

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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