title: Comparative in vivo and in vitro studies with the potent GABAB receptor antagonist, CGP 56999A.
abstract: CGP 56999A ([3-[1-(R)-[(3-cyclohexylmethyl)hydroxyphosphinyl]-2-(S)- hydroxy-propyl] amino]ethyl]-benzoic acid) is a potent GABAB receptor antagonist showing much more pronounced convulsant features in mice than do other previously studied GABAB receptor antagonists. The goal of this study was to elucidate the physiological mechanisms underlying this effect. In mice a dose of 0.6 mg/kg intraperitoneal (i.p.) CGP 56999A elicited behavioral activation and stereotypy with periods of intensive scratching and grooming. At 1 mg/kg i.p. most mice displayed myoclonic seizure-like episodes lasting several min. Pretreatment with the lower dose of 0.6 mg/kg i.p. also induced seizures after treatment with a subthreshold dose of pentylenetetrazole (40 mg/kg i.p.). In rats a dose of 3 mg/kg CGP 56999A (i.p.) induced convulsions of tonic-clonic nature. Intracellular sharp microelectrode recordings from rat cortical neurons in slices revealed no paroxysmal actions of CGP 56999A (10 microM). Similar to other GABAB receptor antagonists, CGP 56999A suppressed the late inhibitory postsynaptic potential (i.p.s.p.), but had no effect on the excitatory postsynaptic potential (e.p.s.p.) in the cortex. In cortical slices exposed to picrotoxin (10 microM), the compound evoked pronounced, spontaneous and intense epileptiform discharges. In conclusion, these findings demonstrated that the convulsive feature of the potent GABAB receptor antagonist, CGP 56999A, may be due to suppression of the late i.p.s.p., which becomes apparent in the intact brain only, whereas this action remains undetected in untreated brain slices. This remarkable discrepancy between in vitro and in vivo may be a consequence either of disruption of neuronal circuits during slice preparation or of the pronounced hyperpolarization of pyramidal neurons, at least in the case of cortical slice preparations.
authors.affiliation: Novartis Pharma Inc., Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Badran
authors.forename: M
authors.initials: M
authors.lastname: Schmutz
authors.forename: H R
authors.initials: HR
authors.lastname: Olpe
mesh_terms: D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects; D003292:Convulsants; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018756:GABA Antagonists / Q000494:pharmacology*; D058788:GABA-B Receptor Antagonists; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects; D010433:Pentylenetetrazole; D010721:Phosphinic Acids / Q000494:pharmacology* / Q000633:toxicity; D010852:Picrotoxin / Q000633:toxicity; D017966:Pyramidal Cells / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced; D013239:Stereotyped Behavior / Q000187:drug effects*
chemical_list: D001418:Baclofen; D003292:Convulsants; D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; D010433:Pentylenetetrazole; D010721:Phosphinic Acids; D010852:Picrotoxin; D018080:Receptors, GABA-B; C102659:CGP 56999A