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 resolved enantiomers of (+/-)-1-1 hydroxy-3-aminopyrrolidone-2 ((+/-)-HA-966) on the electrophysiological properties of dopamine-containing neurons in the substantia nigra of the chloral hydrate anesthetized rat. Both (+)- and (-)-HA-966 produced a dose-dependent reduction in firing rate that eventually resulted in total cessation of spontaneous neuronal activity (ID50 = 5.7 and 57.8 mg/kg i.v., respectively). The inhibitory effects of both drugs were accompanied by a marked increase in the regularity of neuronal firing and a concomitant suppression of bursting activity. Although approximately 10-fold less potent than the (-) enantiomer, the inhibitory effects of (+)-HA-966 were completely antagonized by the centrally active, GABAB receptor antagonist, CGP-35348 (300 mg/kg i.v.). These data suggest that the complementary electrophysiological effects of the enantiomers of (+/-)-HA-966 on nigral dopamine neurons are mediated through a common mechanism of action possibly involving a novel interaction with GABAB receptors.
Shepard
P D
PD
Maryland Psychiatric Research Center, Baltimore 21228, USA.
Connelly
S T
ST
Lehmann
H
H
Grobaski
K C
KC
D000818:Animals; D004305:Dose-Response Relationship, Drug; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D013237:Stereoisomerism; D013378:Substantia Nigra / Q000187:drug effects* / Q000502:physiology
D009943:Organophosphorus Compounds; D011760:Pyrrolidinones; D018080:Receptors, GABA-B; D016194:Receptors, N-Methyl-D-Aspartate; C066430:CGP 35348; C001369:1-hydroxy-3-amino-2-pyrrolidone