A kinetic analysis of the effects of beta-phenylethylamine on the concentrations of dopamine and its metabolites in the rat striatum.
The purpose of this investigation was to determine whether the increase in the dopamine (DA) concentration in the rat striatum after a rapid iv injection of beta-phenylethylamine (PEA) can be quantitatively explained by the alteration of the striatum PEA concentration using a constructed DA metabolism model and to examine whether the time courses of the striatum DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentration can be described by this DA metabolism model. The time courses of PEA concentration in plasma and the striatum were determined by gas chromatography-mass spectrometry. The plasma PEA concentration was described by a two-compartment model with nonlinear elimination kinetics. The striatum PEA concentration was about 10 times higher than the plasma PEA concentration. The time course of the striatum PEA concentration was described by a diffusion-limited model including a Michaelis-Menten type transport system from plasma to the striatum and nonlinear elimination from the striatum. The DA concentration in the striatum increased immediately after PEA injection. In contrast, the DOPAC concentration in the striatum decreased immediately. HVA concentration in the striatum increased gradually. Assuming that the enhancement of DA concentration in the striatum after PEA injection is caused by the competitive inhibition of PEA on the reuptake of DA into DA neuronal terminals (and the metabolism from DA to DOPAC is then competitively inhibited by PEA in the DA neuronal terminals), the relationship between the enhancement of DA concentration and PEA concentration in the striatum was analyzed using a constructed DA metabolism model. The enhancement of the DA concentration in the striatum was described quantitatively by this model. Thus, it was clarified that a quantitative relationship between PEA concentration and the enhancement of DA concentration in the striatum is present after PEA injection. However, the time courses of the striatum DOPAC (lower dose) and HVA (time delay) concentrations could not be described by this model. These results indicated that other factors might be necessary to explain the time courses of the DOPAC and HVA concentrations in the striatum after PEA injection, such as the separate evaluation of the effect of PEA on the reuptake of DA into DA neuronal terminals and on the monoamine oxidase-B (MAO-B) activity in the DA neuronal terminals, and the metabolic pathway from DOPAC to HVA.
Sato
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Department of Pharmaceutics, Niigata College of Pharmacy, Japan.
Tamura
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Kitagawa
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Koshiro
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D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D010627:Phenethylamines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011619:Psychotropic Drugs / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D010627:Phenethylamines; D011619:Psychotropic Drugs; D015102:3,4-Dihydroxyphenylacetic Acid; C029261:phenethylamine; D004298:Dopamine; D006719:Homovanillic Acid