Experimental absence seizures: potential role of gamma-hydroxybutyric acid and GABAB receptors.
We have investigated whether the pathogenesis of spontaneous generalized non-convulsive seizures in rats with genetic absence epilepsy is due to an increase in the brain levels of gamma-hydroxybutyric acid (GHB) or in the rate of its synthesis. Concentrations of GHB or of its precursor gamma-butyrolactone (GBL) were measured with a new GC/MS technique which allows the simultaneous assessment of GHB and GBL. The rate of GHB synthesis was estimated from the increase in GHB levels after inhibition of its catabolism with valproate. The results of this study do not indicate significant differences in GHB or GBL levels, or in their rates of synthesis in rats showing spike-and-wave discharges (SWD) as compared to rats without SWD. Binding data indicate that GHB, but not GBL, has a selective, although weak affinity for GABAB receptors (IC50 = 150 microM). Similar IC50 values were observed in membranes prepared from rats showing SWD and from control rats. The average GHB brain levels of 2.12 +/- 0.23 nmol/g measured in the cortex and of 4.28 +/- 0.90 nmol/g in the thalamus are much lower than the concentrations necessary to occupy a major part of the GABAB receptors. It is unlikely that local accumulations of GHB reach concentrations 30-70-fold higher than the average brain levels. After injection of 3.5 mmol/kg GBL, a dose sufficient to induce SWD, brain concentrations reach 240 +/- 31 nmol/g (Snead, 1991) and GHB could thus stimulate the GABAB receptor. Like the selective and potent GABAB receptor agonist R(-)-baclofen, GHB causes a dose-related decrease in cerebellar cGMP. This decrease and the increase in SWD caused by R(-)-baclofen were completely blocked by the selective and potent GABAB receptor antagonist CGP 35348, whereas only the increase in the duration of SWD induced by GHB was totally antagonized by CGP 35348. The decrease in cerebellar cGMP levels elicited by GHB was only partially antagonized by CGP 35348. These findings suggest that all effects of R(-)-baclofen are mediated by the GABAB receptor, whereas only the induction of SWD by GHB is dependent on GABAB receptor mediation, the decrease in cGMP being only partially so. Taken together with the observations of Marescaux et al. (1992), these results indicate that GABAB receptors are of primary importance in experimental absence epilepsy and that GABAB receptor antagonists may represent a new class of anti-absence drugs.
Bernasconi
R
R
Research and Development Department, Ciba-Geigy, Basel, Switzerland.
Lauber
J
J
Marescaux
C
C
Vergnes
M
M
Martin
P
P
Rubio
V
V
Leonhardt
T
T
Reymann
N
N
Bittiger
H
H
D015107:4-Butyrolactone / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004832:Epilepsy, Absence / Q000378:metabolism / Q000503:physiopathology*; D058787:GABA-A Receptor Antagonists; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains / Q000235:genetics; D011963:Receptors, GABA-A / Q000378:metabolism / Q000502:physiology*; D012016:Reference Values; D015203:Reproducibility of Results; D012978:Sodium Oxybate / Q000302:isolation & purification / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology
D058787:GABA-A Receptor Antagonists; D009943:Organophosphorus Compounds; D011963:Receptors, GABA-A; D014635:Valproic Acid; D012978:Sodium Oxybate; C066430:CGP 35348; D006152:Cyclic GMP; D001418:Baclofen; D015107:4-Butyrolactone