gamma-Hydroxybutyric acid is not a GABA-mimetic agent in the spinal cord.

gamma-Hydroxybutyric acid (GHB), a pharmacologically active central nervous system constituent, has been postulated to function as a gamma-aminobutyric acid (GABA) agonist. This hypothesis was tested directly on GABAergic synapses in isolated, superfused frog spinal cord. Addition of GHB to the superfusate produced effects on primary afferent terminals that were distinctly different from the effects of GABA. Thus, although both compounds depressed dorsal root potentials, GHB hyperpolarized terminals while GABA depolarized the same structures. The GABA responses were antagonized by bicuculline and picrotoxin, but these alkaloids did not change GHB's actions. In addition, GHB altered neither high-affinity uptake by cord slices, nor potassium-evoked release of tritiated GABA from them. GHB did not directly release GABA from spinal slices preloaded with [3H]GABA. These observations suggest that the central nervous system actions of GHB are not dependent upon its ability to activate GABAergic synapses or to modify GABAergic mechanisms.