Relation of the [3H] gamma-hydroxybutyric acid (GHB) binding site to the gamma-aminobutyric acidB (GABAB) receptor in rat brain.
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.
Snead
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Department of Neurology and Pediatrics, University of Southern California, School of Medicine, Los Angeles, USA.
D000818:Animals; D001345:Autoradiography; D001418:Baclofen / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D001567:Benzocycloheptenes / Q000494:pharmacology; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000187:drug effects / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced; D012978:Sodium Oxybate / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000633:toxicity; D013237:Stereoisomerism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D001567:Benzocycloheptenes; D018755:GABA Agonists; D018756:GABA Antagonists; D009943:Organophosphorus Compounds; D018080:Receptors, GABA-B; C061388:3-aminopropylphosphinic acid; C052329:phaclofen; C066471:NCS 382; D005680:gamma-Aminobutyric Acid; D012978:Sodium Oxybate; D006160:Guanosine Triphosphate; C066430:CGP 35348; D001418:Baclofen