Presynaptic GABAB-and gamma-hydroxybutyric acid-mediated mechanisms in generalized absence seizures

gamma-Hydroxybutyric acid (GHB) is a naturally occurring compound which has the ability to induce generalized absence seizures when given to animals. This effect of GHB may be blocked by either GHB or GABAB receptor antagonists. We sought to test the hypothesis that pre-synaptic GHB- and GABAB-mediated mechanisms in thalamus and cortex are operative in the GHB model of generalized absence seizures. Presynaptic Ca(2+)-dependent K+ efflux was determined using Ca(2+)-stimulated Rb86 efflux in synaptosomes prepared from thalamus and cortex in the presence of GHB, a specific GHB receptor antagonist, the specific GABAB agonist (-)baclofen, or the specific GABAB antagonists, phaclofen and CGP 35348. The effect of these compounds was determined also on basal and K(+)-stimulated 45Ca2+ uptake and basal and K(+)-stimulated synaptosomal cytosolic Ca2+([Ca2]i) in synaptosomes prepared from thalamus and cortex and on [125I] omega-conotoxin binding in thalamus and cortex using autoradiographic binding techniques. There was no demonstrable change in Ca(2+)-stimulated Rb86 efflux in any experimental condition studied; however GHB and (-)baclofen both suppressed K(+)-stimulated 45Ca2+ uptake and [Ca2]i in synaptosomes and were associated with a decrease in [125I] omega-conotoxin binding which achieved statistical significance only in frontal cortex, a brain region selectively involved in the genesis of GHB-induced absence seizures. The effects of GHB and (-)baclofen on K(+)-stimulated 45Ca2+ uptake and [Ca2]i in synaptosomes were additive. The effects of GHB in this regard were attenuated by the GHB antagonist and phaclofen while that of (-)baclofen was attenuated by CGP 35348. These data do not support the hypothesis that the GHB and GABAB receptor are one and the same. Rather, they raise the possibility that a presynaptic GHB/GABAB receptor complex might be involved in the pathogenesis of GHB-induced generalized absence seizures.