sodium-oxybate and phaclofen

gamma-Hydroxybutyric acid (GHB) is a naturally occurring compound that has the ability to induce generalized absence seizures when given to animals. GHB has been hypothesized to induce this effect via the postsynaptic gamma-aminobutyric acidB (GABAB) receptor. We sought to test this hypothesis by examining the affinity of GABAB agonists and antagonists for the [3H]GHB binding site, the affinity of GHB and a GHB antagonist for the [3H]GABAB binding site, and the effect of guanine nucleotides and pertussis toxin on both, using autoradiographic binding assays. GHB and its antagonist, NCS 382, did not compete for [3H]GABAB binding, nor did (-)-baclofen or the [3H]GABAB antagonists, CGP 35348 or SCH 50911, compete for [3H]GHB binding; however, the GABAB agonist 3-amino-propylphosphinic acid (3-APPA), and the GABAB antagonists phaclofen and 2-hydroxysaclofen (2-OH saclofen) did show a weak affinity for [3H]GHB binding in frontal cortex. GTP and the nonhydrolyzable GTP analogues, GTP gamma S and Gpp(NH)p, depressed [3H]GABAB binding throughout the brain, but increased [3H]GHB binding in frontal cortex and thalamus, those regions involved in GHB-induced absence seizures. Pertussis toxin significantly depressed [3H]GABAB binding throughout the brain, but attenuated [3H]GHB binding only in frontal cortex, and to a lesser degree than [3H]GABAB binding. The guanine nucleotide-induced changes in [3H]GHB and [3H]GABAB binding were due to a change in KD for both. Moreover, GTP gamma S reversed the ability of 3-APPA, phaclofen, and 2-OH saclofen to compete for [3H]GHB binding. These data do not support the hypothesis that GHB acts through the postsynaptic GABAB receptor to produce absence seizures. Rather, they raise the possibility either that the [3H]GHB binding site may be an isoform of the presynaptic GABAB receptor or that an independent GHB site is operative in the GHB model of absence seizures.

Topics: Animals; Autoradiography; Baclofen; Benzocycloheptenes; Binding Sites; Brain; GABA Agonists; GABA Antagonists; gamma-Aminobutyric Acid; Guanosine Triphosphate; In Vitro Techniques; Male; Organophosphorus Compounds; Rats; Rats, Sprague-Dawley; Receptors, GABA-B; Seizures; Sodium Oxybate; Stereoisomerism

The ventrobasal nucleus of thalamus (VB) is considered to be intimately involved in the genesis of experimental absence-like seizures. Bilateral microinfusion of gamma-hydroxybutyric acid (GHB) into VB or systemic administration of gamma-butyrolactone, the pro-drug of GHB, induces generalized absence-like seizures in rats. In the present study, the basal and K(+)-evoked extracellular output of endogenous gamma-aminobutyric acid (GABA) and glutamate (GLU) in behaving rat VB nucleus was characterized 1) during unilateral GHB perfusion into VB and 2) during the course of generalized absence-like seizures induced by GHB. Although the basal extracellular release of GABA was inhibited by GHB (250-1500 microM) in a concentration-dependent manner, basal GLU levels remained unaltered. However, K(+)-evoked release of both GABA and GLU was significantly attenuated by GHB. During GHB-induced absence-like seizures, a similar decrease in basal GABA or K(+)-evoked GABA and GLU levels was observed. These effects of GHB were partially reversed by the specific GHB receptor antagonist NCS 382. (-)-Baclofen (10-50 microM) also produced a concentration-dependent decrease in basal and K(+)-evoked levels of GABA and GLU in this thalamic nucleus. The effects of either (-)-baclofen or GHB on the release of GABA and GLU were selectively antagonized by the GABAB receptor antagonists phaclofen (0.75-2 mM) and CGP 35348 (50-200 microM), respectively. These results suggest that by selectively modulating the basal and K(+)-evoked release of GABA and GLU, GHB induces, in the thalamic ventrobasal relay nucleus, an optimal "excitatory" environment conducive to the generation of absence seizures. Moreover, the data raise the possibility that a presynaptic GHB/GABAB receptor complex occurs in VB.

Topics: Action Potentials; Animals; Baclofen; Epilepsy, Absence; Extracellular Space; GABA-B Receptor Antagonists; gamma-Aminobutyric Acid; Glutamic Acid; Male; Organophosphorus Compounds; Potassium; Presynaptic Terminals; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, GABA-B; Sodium Oxybate; Thalamic Nuclei