Differential agonist profile of the enantiomers of 3-PPP at striatal dopamine autoreceptors: dependence on extracellular dopamine.
The effects of the enantiomers of 3-hydroxyphenyl-N-n-propylpiperidine (3-PPP) at dopamine (DA) synthesis modulating autoreceptors, measured as DOPA accumulation after decarboxylase inhibition, were assessed in vivo and in rat striatal slices. In vivo, (+)-3-PPP inhibited DOPA accumulation in the striatum, nucleus accumbens, and medial prefrontal cortex, whereas (-)-3-PPP either increased (striatal) or had no effect (accumbens, prefrontal cortex), on DOPA accumulation. In vitro, both (+)- and (-)-3-PPP reduced basal DOPA accumulation with a similar order of potency (apparent EC50 = 2.1 and 1.0 microns, respectively) and maximal effect, although they were less potent than the D2 DA receptor agonist quinpirole (EC50 = 0.15 microM). The inhibition of tyrosine hydroxylation was also observed in slices obtained from reserpine-pretreated rats and was blocked by the selective D2 DA antagonist (-)-sulpiride. This suggests that 3-PPP inhibition of DOPA accumulation was mediated directly by stimulation of DA D2 receptors. Increasing the amount of extracellular DA by depolarizing slices with 30 mM K+ did not alter the qualitative effects of either quinpirole or (+)-3-PPP. However, the stimulation of DA autoreceptors by (-)-3-PPP was no longer apparent under conditions of elevated extracellular DA. Under these depolarizing conditions, (-)-3-PPP actually antagonized the inhibitory effect afforded by either quinpirole or pergolide. A similar switch in profile was observed with transdihydrolisuride (TDHL). The data support the notion that (-)-3-PPP and TDHL are partial agonists at synthesis modulating DA autoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Clark
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Neurochemical Pharmacology Research Unit, Lafayette Clinic, Detroit, Michigan 48207.
Salah
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RS
Galloway
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D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004298:Dopamine / Q000502:physiology*; D004563:Electrochemistry; D004873:Ergolines / Q000494:pharmacology; D066298:In Vitro Techniques; D008090:Lisuride / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D019257:Quinpirole; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D013237:Stereoisomerism
D015306:Biogenic Monoamines; D004873:Ergolines; D009419:Nerve Tissue Proteins; D010880:Piperidines; D011954:Receptors, Dopamine; D019257:Quinpirole; C006208:dironyl; D004295:Dihydroxyphenylalanine; C026539:preclamol; D008090:Lisuride; D011188:Potassium; D004298:Dopamine