GABA

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Death may occur when GABAergic substances are combined with other depressants such as opiates, benzodiazepines, barbiturates, thienodiazepines or alcohol.[1]

It is strongly discouraged to combine these substances, particularly in common to heavy doses.

Skeletal structure of the GABA molecule.

GABA, also known as gamma-aminobutyric acid, is the main inhibitory neurotransmitter. Drugs targeting GABA include benzodiazepines, barbiturates, alcohol and GHB/GBL.

A GABAergic agent is a substance which functions to directly modulate the GABA system, the main inhibitory neurotransmitter, in the body or brain. This can include GABA receptor agonists, GABA receptor antagonists, and GABA reuptake inhibitors.

Substances that indirectly modulate the GABA system are known as "positive allosteric modulators," and includes barbiturates and benzodiazepines as well as alcohol. Flumazenil is an example of a "negative allosteric modulator."[citation needed]

Chemistry

GABA can be classified as an amino acid, a carbon chain with an amine group at one end and then a carboxylic acid at the other. However, as it is not an alpha amino acid, it does not form proteins.

GABA is synthesized from glutamate via the enzyme glutamic acid decarboxylase (GAD). When GABA is released into the synapse, it binds to and activates GABA receptors. This activation is terminated by reuptake back up into the cell that released it and into nearby glial cells. GABA that is taken back into the neuron can be used; however, GABA that enters glia, the supporting cells that surround neurons, cannot be re-synthesized as glial cells lack GAD.

GABA is metabolized by the enzyme GABA transaminase and certain drugs (such as the antiepileptic vigabatrin) have inhibition of this enzyme as their mechanism of action. Eventually, GABA can be recovered by its metabolite succinic semialdehyde which is transformed by succinic semialdehyde dehydrogenase into succinic acid and enters the Krebs cycle, a complicated pathway that begins with glucose. On the other end of the cycle, glutamine emerges and can be transported back to the neuron where it is converted by the enzyme glutaminase into glutamate which can then be remade into GABA via GAD, completing the loop. This loop is called the GABA shunt.[2]

Inhibitory response

When GABA is released, it binds to postsynaptic receptors, causing the opening of ion channels to allow the flow of either negatively charged chloride ions into the cell or positively charged potassium ions out of the cell. This action results in a negative change in the transmembrane potential (usually causing hyperpolarization).

GABA receptors

The most important target receptors for GABA are GABAA and GABAB.

Drugs targeting GABAA

Benzodiazepines

Thienodiazepines

Others

Drugs targeting GABAB

Drugs targeting GABAB are more scarce, chiefly consisting of phenibut, baclofen, GHB, 1,4-Butanediol, 2-methyl-2-butanol and GBL.

GABAergic dependence and withdrawal

Drugs targeting GABA are notoriously addictive and abrupt cessation of chronic usage is not advised, often causing severe physical withdrawal symptoms. Abrupt withdrawal from some GABAergic drugs, such as alcohol or benzodiazepines, can cause seizures or, in the worst case, death.

The balance between glutamate, the most abundant excitatory neurotransmitter, and GABA, the most abundant inhibitory neurotransmitter, is incredibly important for the brain. Prolonged overexposure to inhibitory stimuli leads to receptor downregulation, such as a reduction in the number of GABA receptors. This causes tolerance, which can lead to escalating dosages in a vicious cycle. Upon withdrawal, GABA receptors are too few and far between to counteract glutamate and the resulting "glutamate storm" can cause excitotoxicity and a host of physical and psychological symptoms including muscle tremors, seizures, anxiety, insomnia and depression.

See also

References

  1. Risks of Combining Depressants (Tripsit) | https://tripsit.me/combining-depressants/
  2. GABA Synthesis, Uptake and Release (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/books/NBK27979/