Studies in vivo on the relationship between brain tryptophan, brain 5-HT synthesis and hyperactivity in rats treated with a monoamine oxidase inhibitor and L-tryptophan.

Abstract

Abstract— The effect of l‐tryptophan loading upon the amount of 5‐HT accumulating in the brains of rats pretreated with a monoamine oxidase inhibitor was studied. The amount of brain 5‐HT accumulated increased with increasing tryptophan dosages and brain tryptophan concentrations up to a tryptophan dose of 120 mg/kg body wt. and a brain tryptophan of about 70 μg/g brain. Above this dose and concentration no further increase in brain 5‐HT accumulation occurred. After monoamine oxidase inhibition and tryptophan loading gross hyperactivity and hyperpyrexia occurred. Monoamine oxidase inhibition, tryptophan administration and intact aromatic amino acid decarboxylase activity were all collectively essential for the production of hyperactivity and hyperpyrexia. DL‐Parachlorophenyl‐alanine prevented both the occurrence of hyperactivity and the increased accumulation of, brain 5‐HT. Indices of hyperactivity correlated with the amount of brain 5‐HT accumulating in 1 h after tryptophan loading but not with the overall concentration of brain 5‐HT, suggesting that hyperactivity was dependent upon the rate of 5‐HT synthesis. Reserpine and tetra‐benazine pretreatment speeded the onset and rate of development of the hyperactive state without altering the synthesis of brain 5‐HT. It is suggested that when monoamine oxidase is inhibited and the rate of 5‐HT synthesis is increased, granular uptake and storage of 5‐HT and other rate‐limiting mechanisms for 5‐HT inactivation are unable to prevent 5‐HT 'spilling over’to produce hyperactivity.The crucial dependence of 5‐HT synthesis upon brain tryptophan concentration and the ability of intraneuronal metabolism, when monoamine oxidase activity is intact, to cope with increased 5‐HT synthesis and prevent ‘spillover’, raise the possibility that brain 5‐HT synthesis is normally in excess of functional needs, and suggest that intraneuronal metabolism and the intraneuronal organization of 5‐HT pools are of more importance than synthesis in regulating the amount of 5‐HT available for functional activity.