I've been reading up on some things.
https://en.m.wikipedia.org/wiki/Gamma-Hydroxybutyric_acid
I am reasonably familiar with the classification of receptors, such as GABA acting on 'Ligand-gated ion channels' (GABAA), GPCRs etc.
GHB acts on the 'GHB receptor' https://en.m.wikipedia.org/wiki/GHB_receptor
'The existence of a specific GHB receptor was predicted by observing the action of GHB and related compounds that primarily act on the GABAB receptor, but also exhibit a range of effects which were found not to be produced by GABAB activity, and so were suspected of being produced by a novel and at the time unidentified receptor target. Following the discovery of the "orphan" G-protein coupled receptor GPR172A, it was subsequently found to be the GHB receptor whose existence had been previously predicted.[1] The rat GHB receptor was first cloned and characterised in 2003[2] followed by the human receptor in 2007.'
'The function of the GHB receptor appears to be quite different from that of the GABAB receptor. It shares no sequence homology with GABAB, and administration of mixed GHB/GABAB receptor agonists along with a selective GABAB antagonist or selective agonists for the GHB receptor which are not agonists at GABAB, do not produce a sedative effect, instead causing a stimulant effect followed by convulsions at higher doses, thought to be mediated through increased Na+/K+ current and increased release of dopamine and glutamate.[4][5][6][7][8][9]'
That pretty much leaves the question: what is the GHB receptor for ? Everything has a purpose from the perspective of evolution. GABA is a major inhibitory neurotransmitter, glutamate is a major excitatory neurotransmitter. But GHB ?
According to https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/ghb-receptor:
'(It is an agonist at the ) excitatory G protein-coupled GBH receptor that is widely distributed throughout the brain, with highest receptor density found in the cortex, the hippocampus, the olfactory tracts, and the cerebellum' Somewhat related drugs such as 1,4-Butanediol and GBL and of course GHB have some effects on the brain that are sought after, varying from sedation to sleep to euphoria.
These three drugs are not the same, but different sources depict the drug as either harmless in overdose to lethal, either alone or (the latter) when combined with alcohol.
In a nutshell, my questions:
- is anything known or suspected about the evolutionary origin or function of the GHB receptor?
- what is really known about the distribution in the brain, and how does this receptor interact with other receptors/neurotransmitters ? Are there about as many GHB receptors as GABA receptors, or just a few ? How 'powerful' are these GHB receptors ?
- most sources state that GHB overdose is usually not lethal, unless combined with alcohol or other sedatives. To what extent is there cross tolerance and dependence with benzodiazepines ?
https://en.m.wikipedia.org/wiki/Gamma-Hydroxybutyric_acid
I am reasonably familiar with the classification of receptors, such as GABA acting on 'Ligand-gated ion channels' (GABAA), GPCRs etc.
GHB acts on the 'GHB receptor' https://en.m.wikipedia.org/wiki/GHB_receptor
'The existence of a specific GHB receptor was predicted by observing the action of GHB and related compounds that primarily act on the GABAB receptor, but also exhibit a range of effects which were found not to be produced by GABAB activity, and so were suspected of being produced by a novel and at the time unidentified receptor target. Following the discovery of the "orphan" G-protein coupled receptor GPR172A, it was subsequently found to be the GHB receptor whose existence had been previously predicted.[1] The rat GHB receptor was first cloned and characterised in 2003[2] followed by the human receptor in 2007.'
'The function of the GHB receptor appears to be quite different from that of the GABAB receptor. It shares no sequence homology with GABAB, and administration of mixed GHB/GABAB receptor agonists along with a selective GABAB antagonist or selective agonists for the GHB receptor which are not agonists at GABAB, do not produce a sedative effect, instead causing a stimulant effect followed by convulsions at higher doses, thought to be mediated through increased Na+/K+ current and increased release of dopamine and glutamate.[4][5][6][7][8][9]'
That pretty much leaves the question: what is the GHB receptor for ? Everything has a purpose from the perspective of evolution. GABA is a major inhibitory neurotransmitter, glutamate is a major excitatory neurotransmitter. But GHB ?
According to https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/ghb-receptor:
'(It is an agonist at the ) excitatory G protein-coupled GBH receptor that is widely distributed throughout the brain, with highest receptor density found in the cortex, the hippocampus, the olfactory tracts, and the cerebellum' Somewhat related drugs such as 1,4-Butanediol and GBL and of course GHB have some effects on the brain that are sought after, varying from sedation to sleep to euphoria.
These three drugs are not the same, but different sources depict the drug as either harmless in overdose to lethal, either alone or (the latter) when combined with alcohol.
In a nutshell, my questions:
- is anything known or suspected about the evolutionary origin or function of the GHB receptor?
- what is really known about the distribution in the brain, and how does this receptor interact with other receptors/neurotransmitters ? Are there about as many GHB receptors as GABA receptors, or just a few ? How 'powerful' are these GHB receptors ?
- most sources state that GHB overdose is usually not lethal, unless combined with alcohol or other sedatives. To what extent is there cross tolerance and dependence with benzodiazepines ?