Neurochemical effects of amphetamine metabolites on central dopaminergic and serotonergic systems.
Intrastriatal administration of the hydroxylated metabolites of amphetamine, p-hydroxyamphetamine (p-OHA) or p-hydroxy-norephedrine (p-OHNor), decreased local concentrations of dopamine and serotonin in a dose-dependent manner. Although both compounds reduced concentrations of the metabolites of dopamine, 5-hydroxyindoleacetic acid concentrations were elevated. After systemic treatment with p-OHA, striatal dopamine was also reduced. In contrast, only hypothalamic and hippocampal serotonin stores were altered significantly in rats treated with p-OHA systemically. Neither compound decreased the activities of tryptophan hydroxylase or tyrosine hydroxylase. Because p-OHA is metabolized to p-OHNor via dopamine beta-hydroxylase present in noradrenergic neurons, the direct effects of these compounds on dopaminergic and serotonergic variables can be observed in rats which receive intrastriatal drug treatment. p-OHA and p-OHNor were equally potent in decreasing dopamine concentrations. However, p-OHNor was more potent than p-OHA in decreasing serotonin concentrations. Both compounds more readily depleted dopamine compared to serotonin stores. Complete recovery of p-OHA-induced decreases in striatal dopamine occurred within 48 hr of intrastriatal administration and concurrent treatment with the dopamine uptake blocker, amfonelic acid, significantly attenuated the p-OHA-induced effects on dopamine.
Matsuda
L A
LA
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City.
Hanson
G R
GR
Gibb
J W
JW
D000661:Amphetamine / Q000378:metabolism*; D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000032:analysis / Q000378:metabolism; D008297:Male; D009268:Nalidixic Acid / Q000031:analogs & derivatives; D009287:Naphthyridines / Q000494:pharmacology; D010665:Phenylpropanolamine / Q000031:analogs & derivatives*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000032:analysis / Q000378:metabolism; D013997:Time Factors; D010136:p-Hydroxyamphetamine / Q000494:pharmacology*; D010137:p-Hydroxynorephedrine / Q000494:pharmacology*
D000662:Amphetamines; D009287:Naphthyridines; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D012701:Serotonin; D010665:Phenylpropanolamine; D009268:Nalidixic Acid; D010137:p-Hydroxynorephedrine; D000661:Amphetamine; D010136:p-Hydroxyamphetamine; D003042:Cocaine; C006486:amfonelic acid; D004298:Dopamine