5‐HYDROXYTRYPTAMINE: THE EFFECTS OF IMPAIRED SYNTHESIS ON ITS METABOLISM AND RELEASE IN RAT

Abstract

Control rats given L‐tryptophan (100 mg/kg) showed a smaller increase of brain 5‐hydroxytryptamine (5‐HT) than its metabolite 5‐hydroxyindoleacetic acid (5‐HIAA). However, when brain 5‐HT oncentrations were depleted by 40–50% after treatment with the synthesis inhibitor p‐chlorophenylalanine (PCPA) (150 mg/kg) L‐tryptophan caused a considerable increase in 5‐HT but no change in 5‐HIAA. Similar results were obtained following depletion of brain 5‐HT by pretreatment with p‐chloroamphetamine (10 mg/kg). Electrical stimulation of the median raphe nucleus of control rats significantly increased 5‐HIAA in the hypothalamus, hippocampus and striatum. However, stimulation of PCPA (200mg/kg) pretreated animals did not significantly increase 5‐HlAA either 24 or 72 h after administration of the drug. Pretreatment of rats with PCPA (200 mg/kg) increased striatal synaptosomal uptake of [3H]‐5HT by 30% and reduced 5‐HT concentration in the rest of the brain by 62%. PCPA (150mg/kg) markedly reduced the acute behavioural response (‐76%) to p‐chloroamphetamine (10 mg/kg) although brain 5‐HT was only moderately reduced (‐36%). L‐Tryptophan (100 mg/kg) given 15 min before p‐chloroamphetamine restored both brain 5‐HT and the behavioural effects of p‐chloroamphetamine in PCPA pretreated rats and enhanced the behavioural response to p‐chloroamphetamine in control rats. The results suggest that newly synthesized 5‐HT is less rapidly metabolized in rats with low brain 5‐HT. The possible reasons for this and the relevance of the results to the use of L‐tryptophan in the treatment of depressive illness are discussed. 1978 British Pharmacological Society