EFFECTS OF THE ENANTIOMERS OF (+ -)-HA-966 ON DOPAMINE NEURONS - AN ELECTROPHYSIOLOGICAL STUDY OF A CHIRAL MOLECULE/

The present study was conducted to evaluate the effects of the resolve d enantiomers of (+/-)-1-hydroxy-3-aminopyrrolidone-2 ((+/-)-HA-966) o n the electrophysiological properties of dopamine-containing neurons i n the substantia nigra of the chloral hydrate anesthetized rat. Both()- and(-)-HA-966 produced a dose-dependent reduction in firing rate th at eventually resulted in total cessation of spontaneous neuronal acti vity (ID50 = 5.7 and 57.8 mg/kg i.v., respectively). The inhibitory ef fects of both drugs were accompanied by a marked increase in the regul arity of neuronal firing and a concomitant suppression of bursting act ivity. Although approximately 10-fold less potent than the (-) enantio mer, the inhibitory effects of (+)-HA-966 were completely antagonized by the centrally active, GABA(B) receptor antagonist, CGP-35348 (300 m g/kg i.v.). These data suggest that the complementary electrophysiolog ical effects of the enantiomers of (+/-)-HA-966 on nigral dopamine neu rons are mediated through a common mechanism of action possibly involv ing a novel interaction with GABA(B) receptors.