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On the interaction of 5-hydroxytryptophan and 5-hydroxytryptamine with dopamine metabolism in the rat striatum


The effects of 5-hydroxytryptophan (5-HTP) and some indole derivatives on dopamine metabolism in the corpus striatum of rat were studied. Striatal dopamine as well as its metabolic end-products, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured following 5-HTP or other indoles administered systemically or intraventricularly under different experimental conditions. Dopamine synthesis-rate was measured by using 3H-tyrosine and estimating the amount of radioactive label incorporated into striatal dopamine.

  1. 1.

    D,L-5-HTP given to rats in doses of 64.5 mg/kg i.p. or 0.5\2-5 \gmg intraventricularly induced a rapid fall in striatal dopamine and an early rise in the DOPAC and HVA concentrations.

  • The initial fall in dopamine concentration at 1 h was followed by a significant rise at 6 h after the 5-HTP administration.

  1. 2.

    Long-term administration of 5-HTP (64.5 mg/kg, i.p., twice daily for 14 days) caused a sustained decrease in striatal dopamine and the HVA concentration was initially lower than controls.

  2. 3.

    While a single dose of 5-HTP given systemically (64.5 mg/kg i.p.) or intraventricularly (\s> 2 \gmg) caused an elevation of striatal 5-HT levels, the chronic administration of 5-HTP led to no such rises in brain 5-HT; in fact, the levels were below normal. Monoamine oxidase activity in the striatum was unaffected by the long-term 5-HTP administration.

  3. 4.

    Graded doses of D,L-5-HTP (range: 0.5\2-150 \gmg intraventricularly) caused a dose-dependent increase in striatal 5-HT concentrations at 1 h following the drug administration. The dopamine concentrations in the striatum were reduced with the lower doses (0.5\2-5 \gmg) of 5-HTP while at higher dose levels (15\2-150 \gmg) dopamine concentrations were elevated above control values. An increase in the concentrations of dopamine metabolites, DOPAC and HVA, was observed for different doses of 5-HTP at 1 h after its administration.

  4. 5.

    After a short i.v. infusion of 3H-tyrosine (about 200 \gmCi), the 3H-dopamine accumulation in the rat striatum was reduced in animals treated with D,L-5-HTP (0.5 or 75 \gmg, intraventricularly) 40 min before the 3H-tyrosine infusion.

  • On the other hand, in rats treated with D,L-5-HTP (0.5, 2.5 or 5 μg) 340 min before the infusion of 3H-tyrosine, significant rises in the labelled dopamine fractions were found.

  1. 6.

    Gamma-hydroxybutyrate (GHB) in a dose of 750 mg/kg i.p. produced an increase in striatal dopamine and a decrease in HVA concentrations.

  • When GHB (administered 90 min prior to killing the rats) was given 30 min before 5-HTP (2 μg intraventricularly), the dopamine depletion induced by 5-HTP alone was found to be unaffected by the GHB pretreatment. GHB pretreatment affected the rise in striatal HVA concentration caused by 5-HTP alone.

  1. 7.

    5-hydroxytryptamine (5-HT) injected intraventricularly to rats in a dose of 0.5 \gmg caused a reduction in striatal dopamine, HVA and DOPAC concentrations for 1\2-6 h after its administration. The dose-effect curve showed an increasing effect of 5-HT (dose range: 0.1\2-1.0 \gmg) on dopamine metabolism.

  2. 8.

    Indole derivatives, tryptophan, tryptamine, 6-hydroxytryptamine, 5-methoxytryptamine, 5-hydroxyindoleacetic acid, in doses of 0.4\2-0.5 \gmg intraventricularly had different effects on striatal dopamine concentrations: tryptophan had no effect; tryptamine caused a decrease; while 5-hydroxyindoleacetic acid caused a decrease followed by an increase.

  3. 9.

    The mode of action of 5-HTP on striatal dopamine was considered to be that of displacement of dopamine from storage sites and metabolism following intraneuronal release of the amine. This action led in turn to a compensatory dopaminergic mechanism operating by a positive feed-back on the rate-limiting step in dopamine synthesis and increasing the rate of formation of the amine.

    • It seemed likely that the mechanism of action of exogenous 5-HT on striatal dopamine was different from that of 5-HTP and it was proposed that 5-HT acted primarily by inhibiting the synthesis of dopamine. However, this effect could under certain experimental conditions also be observed after 5-HTP administration.

    • It is postulated that the essential difference in the mode of action of 5-HTP and 5-HT on dopamine might be that 5-HTP is readily taken up by dopaminergic neurones and decarboxylated to 5-HT which in turn displaces dopamine from the stores. On the other hand, exogenous 5-HT is poorly taken up by dopaminergic neurones and exerts its effects on dopamine by its action through serotonergic neurones.

  4. 10.

    It was considered that the effect of 5-HTP, but not tryptophan, observed in the present experiments on striatal dopamine, makes it necessary to reexamine observations based on the use of 5-HTP to elucidate the role of 5-HT in some motor and behavioural functions. These supposed effects of 5-HTP on 5-HT neurones may at least in part by mediated through the dopaminergic system.

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Correspondence to H. C. Guldberg.

Additional information

Most of this work was done while Noriko Awazi and H. C. Guldberg were members of staff of the Department of Pharmacology, University of Bergen, Bergen, Norway

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Awazi, N., Guldberg, H.C. On the interaction of 5-hydroxytryptophan and 5-hydroxytryptamine with dopamine metabolism in the rat striatum. Naunyn-Schmiedeberg's Arch. Pharmacol. 303, 63–72 (1978).

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Key words

  • 5-Hydroxytryptophan
  • 5-Hydroxytryptamine
  • Dopamine
  • Monoaminergic interactions