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.

Interaction in the cerebral metabolism of the biogenic amines. Effects of phenelzine on the cerebral metabolism of the 5‐hydroxyindoles in dog brain

“…These findings and recent experiments concerning the relation of cerebral 5-hydroxytryptamine to a syndrome of hyperactivity and hyperpyrexia (Grahame-Smith, 1971) would suggest that the model previously proposed for cerebral 5-hydroxytryptamine metabolism (Moir & Eccleston, 1968) should be modified. The diagram shown in Fig.…”

The Effects of Putative 5‐hydroxytryptamine Antagonists on the Behaviour Produced by Administration of Tranylcypromine and L‐tryptophan or Tranylcypromine and L‐dopa to Rats

“…Crow & Deakin (1977) suggested that the different behavioural components of the tranylcypromine/tryptophan syndrome might have different neurochemical bases. Conflicting experimental results might thus be explained by methods of quantification of the behaviour which emphasize different behavioural components, for example, automated recordings of activity (Grahame-Smith, 1971a) and ratings of headweaving and forepaw treading etc. (Jacobs, 1974).…”

“…The behaviour appears to be due to increased synthesis and 'spill-over' onto the postsynaptic receptors of brain 5-hydroxytryptamine (5-HT) (Grahame-Smith, 1971a); the behavioural changes have been used to investigate the way that various drugs alter 5-HT function in the central nervous system (see reviews of Green & Grahame-Smith, 1976a;Jacobs, 1976).…”

“…When rats are treated with an irreversible monoamine oxidase (MAO) inhibitor and L-tryptophan they display a complex series of behavioural changes which includes hyperactivity (Hess & Doepfner, 1961;Grahame-Smith, 1971a). The behaviour appears to be due to increased synthesis and 'spill-over' onto the postsynaptic receptors of brain 5-hydroxytryptamine (5-HT) (Grahame-Smith, 1971a); the behavioural changes have been used to investigate the way that various drugs alter 5-HT function in the central nervous system (see reviews of Green & Grahame-Smith, 1976a;Jacobs, 1976).…”

The Influence of L‐tryptophan and Monoamine Oxidase Inhibitors on Catecholamine Metabolism in Rat Brain

“…In animals the administration of a combination of L-tryptophan and a monoamine oxidase inhibitor leads to a characteristic behavioural syndrome (Hess Doepfner, 1961;Grahame-Smith, 1971), which in rats may be subdivided into various components including hyperactivity, hyper-reactivity, reciprocal forepaw treading, headweaving and hind limb abduction. A dopaminergic component of the syndrome has been proposed (Green & Grahame-Smith, 1974) on the basis of the inhibition of the syndrome by pretreatment of the animals with a-methyl-p-tyrosine, a drug which blocks the synthesis of dopamine.…”