(+-)-1-hydroxy-3-aminopyrrolidone-2 (HA-966) inhibits the activity of substantia nigra dopamine neurons through a non-N-methyl-D-aspartate receptor-mediated mechanism.
(+-)-1-hydroxy-3-aminopyrrolidone-2 [(+/-)-HA-966] is known to cause a rapid and selective increase in striatal dopamine (DA) levels--an effect that has been attributed to the compound's presumed ability to block the spontaneous electrical activity of nigrostriatal DA neurons. In the present series of experiments, extracellular single unit recording techniques were used to explore this premise in the chloral hydrate-anesthetized rat and to compare the pharmacological effects of the racemic form of HA-966 with its resolved enantiomers. Systemic administration of (+/-)-HA-966 produced a dose-dependent inhibition in the firing rate of DA neurons in the zona compacta of the substantia nigra. The highest dose tested (40 mg/kg i.v.) completely inhibited the spontaneous activity of all cells tested. Pretreatment with naloxone (5 or 10 mg/kg i.v.) reduced the initial rate of decline in firing rate and the duration of inhibition but did not prevent a single dose of 40 mg/kg of (+/-)-HA-966 from totally inhibiting DA cell impulse flow. Systemic administration of the (-)-enantiomer of HA-966 (30 mg/kg i.v.) inhibited neuronal activity in a manner analogous to a single injection of 40 mg/kg of (+/-)-HA-966. Comparable doses of the (+)-enantiomer failed to affect significantly the firing rate of substantia nigra DA neurons but suppressed bursting activity and "normalized" neuronal discharge pattern.(ABSTRACT TRUNCATED AT 250 WORDS)
Shepard
P D
PD
Maryland Psychiatric Research Center, Baltimore.
Lehmann
H
H
D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D004347:Drug Interactions; D004594:Electrophysiology; D007275:Injections, Intravenous; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism
D011760:Pyrrolidinones; D009270:Naloxone; C001369:1-hydroxy-3-amino-2-pyrrolidone; D004298:Dopamine