COMPARATIVE IN-VIVO AND IN-VITRO STUDIES WITH THE POTENT GABA(B) RECEPTOR ANTAGONIST, CGP 56999A

CGP 56999A sphinyl]-2-(S)-hydroxy-propyl]amino]ethyl]-benzoic acid) is a potent GABA(B) receptor antagonist showing much more pronounced con vulsant features in mice than do other previously studied GABA(B) rece ptor antagonists. The goal of this study was to elucidate the physiolo gical mechanisms underlying this effect. In mice a dose of 0.6 mg/kg i ntraperitoneal (i.p.) CGP 56999A elicited behavioral activation and st ereotypy with periods of intensive scratching and grooming. At 1 mg/kg i.p. most mice displayed myoclonic seizure-like episodes lasting seve ral min. Pretreatment with the lower dose of 0.6 mg/kg i.p. also induc ed seizures after treatment with a subthreshold dose of pentylenetetra zole (40 mg/kg i.p.). In rats a dose of 3 mg/kg CGP 56999A (i.p.) indu ced convulsions of tonic-clonic nature. Intracellular sharp microelect rode recordings from rat cortical neurons in slices revealed no paroxy smal actions of CGP 56999A (10 mu M). Similar to other GABA(B) recepto r 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 pic rotoxin (10 mu M), the compound evoked pronounced, spontaneous and int ense epileptiform discharges. In conclusion, these findings demonstrat ed that the convulsive feature of the potent GABA, receptor antagonist , CGP 56999A, may be due to suppression of the late i.p.s.p., which be comes apparent in the intact brain only, whereas this action remains u ndetected in untreated brain slices. This remarkable discrepancy betwe en in vitro and in vivo may be a consequence either of disruption of n euronal circuits during slice preparation or of the pronounced hyperpo larization of pyramidal neurons, at least in the case of cortical slic e preparations. (C) 1997 Elsevier Science B.V.