The metabolism of GABA in brain generates bioactive metabolites as well as substrates for the carboxylic acid cycle (e.g. succinate). The enzyme aldehyde reductase was discovered in 1974 and was shown to produce gamma-hydroxybutyrate (GHB) in the brain.
Sodium oxybate, also known as GHB, had already gained popularity at that time as a xenobiotic with anesthetic properties, and the discovery of the natural production of GHB in brain spurred the search for receptors for the naturally occurring and exogenously administered GHB in the brain and other organs.
The current evidence indicates that there are two distinct types of receptors for GHB. One is the GABAB receptor dimer, and the other is a GHB-binding protein whose physiological role is still obscure. Both of these ‘receptors’ are G-protein-coupled receptors exerting their function via interaction with the Gi/Go protein family. Selective antagonists are available for these receptor types (CGP54626 for the GABAB receptor and NCS-382 for the GHB binding protein) and GABAB receptor null mutant mice have been created. Using these resources, the actions of GHB have been shown to have components that cannot be adequately explained only through the GABAB receptor.
Interest in the biology of GHB has been increased by both its use as a ‘recreational’ drug and its more recent application as a treatment for addictive disorders, particularly alcoholism. GHB has been shown to be an effective agent for treating alcohol withdrawal and supporting abstinence over the early period of sobriety, but concern remains about its abuse potential.
Recent data on the importance of GABA neurotransmission in genetic predisposition to alcohol consumption, as well as on GHB-induced neuro-adaptation which may regulate self-administration of alcohol in animal models, make further inquiry into GHB actions in addiction attractive and necessary.
Let’s continue to seek treatments which include sodium that reduce withdrawal and increase abstinence.
