Significance of gamma-hydroxybutyric acid in the brain.

1. Administration of the endogenous compound gamma-hydroxybutyric acid (GHB) can induce a sleep-like state in experimental animals and, indeed, it has been used as a general anaesthetic in clinical medicine. 2. Although GHB appears to be a CNS depressant, there is evidence it possesses epileptiform activity resembling petit mal epilepsy. In the brain GHB is evidently derived from GABA, the final step being catalyzed by succinic semialdehyde reductase, a cytosolic NADP(+)-dependent enzyme. 3. Two different oxidoreductases, GHB dehydrogenase and hydroxyacid-ketoacid dehydrogenase, acting independently, are responsible for the reverse reaction when GHB is being metabolically inactivated. 4. Brain contains a Na(+)-dependent GHB uptake system which exhibits two components, one with a Km of 46 microM and the other with a Km of 325 microM. GHB also binds to receptor sites in brain homogenates and exhibits two distinct affinities. One binding site displays a Kd of 95 nM whereas the second site has a Kd of 16 microM. Binding to both sites is inhibited in the presence of NCS-382, a GHB receptor antagonist. 5. GHB might play a role as a neurotransmitter, particularly being involved in influencing dopamine release in the substantia nigra.