Studies on the relation of gamma-hydroxybutyric acid (GHB) to gamma-aminobutyric acid (GABA). Evidence that GABA is not the sole source for GHB in rat brain.

The effects of gamma-aminobutyric acid (GABA)-alpha-oxoglutarate aminotransferase (GABA-T) inhibitors, L-glutamic acid decarboxylase (GAD) inhibitors, and antipetit mal anticonvulsants on gamma-hydroxybutyric acid (GHB) and GABA were studied. Treatment with anticonvulsants and GABA-T inhibitors resulted in an increase in steady-state brain levels of both GHB and GABA. GAD inhibitors produced markedly decreased levels of brain GABA but no change in GHB concentrations. Studies of GHB derived exclusively from GABA showed that GABA-T inhibitors which produced an elevation of steady-state levels of GHB in brain also resulted in a decrease in GABA-derived GHB. Intracerebroventricular (i.c.v.) administration of GABA, putrescine, and 1,4-butanediol all produced significant elevations in brain GHB, but GABA-T inhibitors blocked this effect of GABA and putrescine. These data suggest that there may be another source for GHB in brain in addition to GABA and raise the possibility that 1,4-butanediol may be that source.

The epileptogenic spectrum of opiate agonists.

The present authors gave mu, delta, kappa, epsilon and sigma opiate receptor agonists intracerebroventricularly to rats both singly and in combination while monitoring the electroencephalogram from cortical and depth electrodes. Dose-response curves were plotted with naloxone against the changes produced by each agonist, and the effect of a number of anticonvulsant drugs on agonist-induced seizures was ascertained. Each opiate agonist produced a different seizure pattern with a different naloxone dose-response curve and anticonvulsant profile. The order of convulsive potency was epsilon greater than delta greater than mu greater than sigma much greater than kappa. Petit mal-like seizure activity was unique to the delta agonist, leucine-enkephalin, while only the mu agonist, morphine produced generalized convulsive seizures. These experiments raise the possibility that opiate systems in the brain may be involved in the pathogenesis of a wide spectrum of seizure disorders.

Anticonvulsants specific for petit mal antagonize epileptogenic effect of leucine enkephalin.

The anticonvulsants ethosuximide, sodium valproate, and trimethadione that are specific for petit mal epilepsy abolished in rats the electrical seizure activity and behavioral abnormalities produced by leucine enkephalin, whereas phenobarbital and phenytoin had no effect. The dose-response curve for naloxone against seizure activity induced by leucine enkephalin was the same as that in gamma-hydroxybutyrate-induced petit mal. These data indicate that the epileptic properties of leucine enkephalin are petit mal-like and raise the possibility of involvement of enkephalinergic systems in. The dose-response curve for naloxone against seizure activity induced by leucine enkephalin was the same as that in gamma-hydroxybutyrate-induced petit mal. These data indicate that the epileptic properties of leucine enkephalin are petit mal-like and raise the possibility of involvement of enkephalinergic systems in petit mal epilepsy.

Naloxone overcomes the dopaminergic, EEG, and behavioral effects of gamma-hydroxybutyrate.

The specific opiate antagonists--naloxone and naltrexone--attenuated or abolished the electrical seizure activity, behavioral abnormalities, and increased striatal dopamine content produced by gamma-butyrolactone, the prodrug of gamma-hydroxybutyrate. The effects of naloxone and naltrexone were dose-dependent. These data suggest that gamma-hydroxybutyric acid exerts its effects by action either at the opiate receptor or on enkephalinergic systems, which may be involved in petit mal epilepsy.

Antagonism of gamma-hydroxybutyric acid-induced frequency shifts in the cortical EEG of rats by dipropylacetate.

An automated technique for the continuous analysis of selected EEG frequency bands as a function of drug treatment is described. Experiments utilizing this analytical method have shown that the convulsive effects of GHB are antagonized by dipropylacetate, but that the effects of GHB exhibit a latent irreversibility.

Growth inhibition of cultured fibroblasts by cobalt and nickel.

It is known that tissues surrounding the site of an implanted prosthetic alloy are exposed to increased concentrations of the metals comprising the alloy. However, the exact identity and concentration of such metallic products are usually unknown, thus limiting the possibilities for quantifying any observed toxicological response to the metals. This report describes some of the effects of increased concentrations (7.5-30 microgram/ml; 1-5 x 10(-4)M) Of cobalt (as CoCl2.6H2O) and of nickel (NiCl2.6H2O) on the growth and morphology of cultured mouse fibroblasts. Ultrafiltration experiments indicated that much of the total Co or Ni present in cell culture medium could become bound to macromolecular serum components of the medium. Morphological changes and depressions in the cell growth rate were found to result from high concentrations (15-30 microgram/ml) of either Co or Ni. However, lower concentrations of nickel may have produced some stimulation of cell growth, whereas all concentrations of Co studied were found to depress the rate of cell growth. The growth rate of actively proliferating fibroblasts was quite sensitive to variations in the concentration of either cobalt or nickel. Increased concentrations of cobalt or nickel, therefore, might also affect the normal reconstructive activity of fibroblasts in vivo.