p-Chlorophenylalanine depletes brain serotonin and induces longlasting sexual excitation in male rats. The effect of p-chlorophenylalanine is potentiated by pargyline. Administration of 5-hydroxytryptophan to rats treated with p-chlorophenylalanine plus pargyline blocks the sexual excitation. p-Chlorophenylalanine also elicits sexual excitation in pinealectomized rats; this effect is not mediated by the lack of indole hormones in the pineal but may be the consequence of depletion of 5-hydroxytryptophan in the brain and the resulting imbalance between 5-hydroxytryptophan and catecholamine activity in the central nervous system.
Cyclic AMP and dibutyryl‐cyclic AMP, a derivative of cyclic AMP resistant to phosphodiesterase inactivation, were injected into the lateral ventricles of rats. These nucleotides did not change the level of brain 5‐HT but increased the brain level of its principal metabolite, 5‐hydroxyindoleacetic acid. Cyclic AMP was less potent than dibutyryl‐cyclic AMP. Butyrate and 5′‐AMP were inactive. The effect of dibutyryl cyclic AMP on 5‐HT metabolism was studied both in vivo and in vitro. The rate of synthesis of 5‐HT was measured by the rate of accumulation of 5‐hydroxyindoleacetic acid after the transport of this acid out of the brain was blocked with probenecid. The rate of synthesis of brain 5‐HT increased from 0‐38 μg/g/h in control rats to 0‐65 μg/g/h after dibutyryl‐cyclic AMP. In addition cyclic AMP and dibutyryl‐cyclic AMP markedly increased brain tryptophan, while AMP was inactive. Since brain tryptophan hydroxylase has a Km for its substrate that is much higher than the concentrations of tryptophan normally present in the brain, it is likely that the increase in the rate of synthesis of brain 5‐HT is secondary to the cyclic AMP induced increase in the levels of brain tryptophan. In vitro studies revealed that dibutyryl‐cyclic AMP increased the uptake of radioactive labelled tryptophan into slices of rat brain stem and the formation of 5‐HT and 5‐hydroxyindoleacetic acid.
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