Effects of d-amphetamine on dopaminergic neurotransmission; a comparison between the substantia nigra and the striatum.
The effects of d-amphetamine (d-AMP) on dopaminergic neurotransmission in the cell body/dendritic region of the nigrostriatal pathway, the substantia nigra, have been investigated and compared to the effects obtained in the terminal region of the pathway, the striatum. The rate of synthesis of dopamine (DA) was quantified as accumulation of 3,4-dihydroxyphenylalanine (DOPA), after inhibition of aromatic L-amino acid decarboxylase with 3-hydroxybenzyl-hydrazine (NSD 1015). As measures of the metabolism of DA the concentrations of the metabolites of DA, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) were determined. As indices of release of DA, the accumulation of 3-methoxytyramine (3-MT), after inhibition of monoamine oxidase with pargyline and the disappearance of DA, after inhibition of its synthesis with alpha-methyl-p-tyrosine were assessed. d-Amphetamine insignificantly increased the concentration of DA in the striatum but profoundly decreased it in the substantia nigra (to 60% of controls). Both in the striatum and in the substantia nigra treatment with d-AMP induced clearcut decreases of the concentrations of DOPAC. Also the concentration of HVA was profoundly decreased in the striatum but only marginal effects on HVA were observed in the substantia nigra. In both structures of the brain, d-AMP increased the concentration of 3-MT. Depending on the dose, d-AMP increased or had no effect on the accumulation of DOPA in the striatum but consistently decreased it in the substantia nigra. In the striatum, d-AMP increased the pargyline-induced accumulation of 3-MT, without affecting the concentration of DA. However, in the substantia nigra the concentration of DA was profoundly decreased (to 50% of controls) in combination with unaltered accumulation of 3-MT, unless the rats were pretreated with haloperidol. If so, the effects of d-AMP on the concentration of DA and accumulation of 3-MT were the same in the substantia nigra and in the striatum. The results indicate that d-AMP depleted stores of DA in the substantia nigra, due to its releasing action, in combination with its decreasing effect on the rate of synthesis of DA. The decrease in rate of synthesis of DA is suggested to be due to the d-AMP-induced decrease in the firing rate of dopaminergic neurones.
Elverfors
A
A
Department of Pharmacology, University of Göteborg, Sweden.
Nissbrandt
H
H
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D003913:Dextroamphetamine / Q000494:pharmacology*; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006719:Homovanillic Acid / Q000378:metabolism; D006834:Hydrazines / Q000494:pharmacology; D008297:Male; D009928:Organ Specificity; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects*
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D006834:Hydrazines; D015102:3,4-Dihydroxyphenylacetic Acid; C004297:3-hydroxybenzylhydrazine; C001746:3-methoxytyramine; D003913:Dextroamphetamine; D004298:Dopamine; D006719:Homovanillic Acid