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GHB Neuropharmacology
by Five
Erowid Note: This article, written in 1996, is now very out of date and contains information no longer believed to be accurate. A more current article on GHB's Pharmacology can be found under GHB Pharmacology.

Sometime ago, I decided to investigate exactly how GHB (gamma-hydroxybutrate) acts on the brain. I had assumed that it involved the GABAnergenic system because of their similar structures- GABA is gamma-aminobutyric acid, so they essentially differ by a NH2 and an OH (I'll spare you my ASCII molecular renditions).

This turns out not to be the case. GHB actually affects the dopamine (DA) system by preventing its release (dispersion) at the synapse. The end result is a reversable lesion (*) in the nigrostriatal and mesolimbic DA systems. Thus, a large enough dose makes a great anestetic by shutting down a rather important (at lease for consciousness) part of the brain.

Additionally, GHB also causes the neurons to make more DA. So now you've plugged the drain *and* turned up the faucet. One wonders what might happen if things were taken to the extreme: A subject (such as a rat) ingests L-DOPA to increase they available precursor for DA, ingests GHB to turn-over this precursor and accumulate it presynaptically, and, finally, applys a combination of amphetamine to release this flood of DA and cocaine to prevent its reuptake (**).

Two other interesting bits of information I located: There is another compound that seems to have the same properties as GHB. Its called (+)-HA-966. (***) I could not seem to find a structure nor additonal information on it. Anyone? Secondly, GHB is "a naturally occuring metabolite" found in the brain. This should ease some worries. Although, I read about a "rare inborn mutation in the metabolism of GABA" called GHB aciduria. It is "unclear whether the ... main clinical symptoms of motor and mental retardation... [are] related to elevated levels of GHB". This should strengthen worries about its toxicity.


mostly "The Biochemical Basis of Neuropharmacology", 7th ed. by Cooper, et. al.

(*)- A "revesible lesion" does not mean that any sort of physical damage has happened to the brain. Rather, it is the temperary "turning off" of an area.
(**)- The author takes no legal or health responsiblities from this suggestion.
(***)- E-mail response to (+)-HA-966 mention :

"Searching with Altavista produced this page:
Review articles describing the NMDA-receptor
which says: "In the present experiments, the discriminative stimulus effects of (+)-HA-966 [R-(+)-3-amino-1-hydroxypyrrolid-2-one), a low-efficacy partial agonist of the glycine site, was explored."

Also, searching in other site found these references:

UI - 001671
Singh L , Menzies R , Tricklebank MD
The discriminative stimulus properties of (+)-HA-966, an antagonist at the glycine/N-methyl-D-aspartate receptor Eur J Pharmac 1990;186:129-132 1990

UI - 002249
Witkin JM , Steele TD , Geter-Douglass B , Tortella FC
Preclinical pharmacology of ligands acting at the strychnine-insensitive glycine receptor of the NMDA receptor Behavioural Pharmacology 1995;6:636-0 1995

UI - 002302
Wiley JL , Balster RL
Discriminative stimulus effects of site-selective NMDA antagonists in NPC 17742-trained rats Behavioural Pharmacology 1995;6:635-0 1995

UI - 002236
Witkin JM , Brave S , French D , Geter-Douglass B
Discriminative stimulus effects of R-(+)-3-amino-1-hydroxypyrrolid-2-one, [(+)-HA-966], a partial agonist of the strychnine-insensitive modulatory site of the n-methyl-d-aspartate receptor J Pharmac Exp Ther 1995;275:1267-1273 1995

UI - 002190
Baron SP , Woods JH
Competitive and uncompetitive N-methyl-d-aspartate antagonist discriminations in pigeons: CGS 19755 and phencyclidine Psychopharmacology 1995;118:42-51 1995

Anyway for the info on these pages this compound does not seem a GHB replacement."