ncs-382 and phaclofen

Hydroxybutyric acid (GHB) is a naturally occurring compound that has the ability to induce generalized absence seizures possibly by GABAB-receptor-mediated mechanisms. The object of these experiments was to examine the effectiveness of a range of specific GABAB-receptor agonists and antagonists of varying specificity, as well as the specific GHB-receptor antagonist NCS 382, in two experimental animal models of generalized absence seizures: one in which the seizures are induced by GHB and the other in which the seizures are induced by administration of low-dose (20-mg/kg) pentylenetetrazole. All specific GABAB-receptor antagonists as well as the specific GHB-receptor antagonist produced blockade of experimental absence seizures in both models; pretreatment with GABAB-receptor agonists resulted in generalized absence status epilepticus lasting for hours. These data confirm the concept that specific GABAB-receptor antagonist activity confers antiabsence seizure activity, suggest that the same holds for specific GHB-receptor antagonists, and raise the possibility that both GHB- and GABAB-antagonist drugs have the potential to be useful therapeutic agents in generalized absence seizures.

Topics: Animals; Anticonvulsants; Baclofen; Benzocycloheptenes; Electroencephalography; Epilepsy, Absence; GABA Agonists; GABA Antagonists; GABA-B Receptor Antagonists; Injections, Intraventricular; Isomerism; Male; Pentylenetetrazole; Rats; Rats, Sprague-Dawley

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