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

Summary

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. 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• 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.