Presynaptic GABA B-and γ-hydroxybutyric acid-mediated mechanisms in generalized absence seizures

Abstract

γ-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 GABA B receptor antagonists. We sought to test the hypothesis that pre-synaptic GHB- and GABA B-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 Rb 86 efflux in synaptosomes prepared from thalamus and cortex in the presence of GHB, a specific GHB receptor antagonist, the specific GABA B agonist (−)baclofen, or the specific GABA B antagonists, phaclofen and CGP 35348. The effect of these compounds was determined also on basal and K +-stimulated 45Ca 2+ uptake and basal and K +-stimulated synaptosomal cytosolic Ca 2+([Ca 2] i) in synaptosomes prepared from thalamus and cortex and on [ 125I]ω-conotoxin binding in thalamus and cortex using autoradiographic binding techniques. There was no demonstrable change in Ca 2+-stimulated Rb 86 efflux in any experimental condition studied; however GHB and (−)baclofen both suppressed K +-stimulated 45Ca 2+ uptake and [Ca 2] i in synaptosomes and were associated with a decrease in [ 125I]ω-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 45Ca 2+ uptake and [Ca 2], 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 GABA B receptor are one and the same. Rather, they raise the possibility that a presynaptic GHB/GABA B receptor complex might be involved in the pathogenesis of GHB-induced generalized absence seizures.