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.

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1We have retrospectively analysed data collected by a local adverse drug reactions reporting scheme in an acute hospital medical setting and have determined the numbers and types of reactions that would have merited notification as yellow card reports according to the guidelines of the Committee on Safety of Medicines. 2The data related to 20 695 consecutive acute general medical admissions on seven general medical wards (140 beds) and were collected over 3 years, from April 1990 to March 1993. 3Over 3 years there were 1420 reports of suspected adverse drug reactions, a rate of 68.7 per 1000 admissions. 4If the guidelines for reporting issued by the Committee on Safety of Medicines had been strictly followed, 477 yellow cards would have been sent (23.1 per 1000 admissions). In 357 of these reports (74.8%), the reaction had caused admission to hospital. Only 31 of the 477 potential cards (6.5%) involved black triangle drugs and 10 of these were for minor reactions. 5Only 30 of the 477 potential yellow cards (6.3%) were known to have been sent. The majority of those reactions not reported were for drug‐related admissions, most of which were for well‐known reactions to established drugs. 6We have confirmed and quantified the extent of under‐reporting of serious suspected adverse drug reactions to the Committee on Safety of Medicines from our hospital medical unit.

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Administration to rats of LiCl (3 mEq/kg) subcutaneously twice daily for 3 days followed by monoamine oxidase inhibition with either tranylcypromine (TCP; 20 mg/kg) or pargyline (75 mg/kg) on the fourth day produces a syndrome of hyperactivity indistinguishable from that produced by monoamine oxidase inhibition and l‐tryptophan administration. At least 3 injections of LiCl (3 mEq/kg) are necessary before hyperactivity is seen but one dose of LiCl (10 mEq/kg) 5 h before TCP also caused hyperactivity. The hyperactivity is blocked by prior administration of p‐chlorophenylalanine, a tryptophan hydroxylase inhibitor. LiCl pretreatment does not alter the concentration of l‐tryptophan in the brain. However after monoamine oxidase inhibition the 5‐hydroxytryptamine (5‐HT) accumulation was significantly greater in animals given lithium indicating an increase in 5‐HT synthesis of 70%. This was confirmed by measuring 5‐hydroxyindoleacetic acid accumulation after probenecid (200 mg/kg). The hyperactivity produced by the 5‐HT analogue, 5‐methoxy N,N‐dimethyltryptamine was not potentiated by lithium pretreatment but one injection of LiCl (3 mEq/kg) which did not alter the rate of 5‐HT synthesis, did potentiate the hyperactivity following TCP (20 mg/kg) and l‐tryptophan (50 mg/kg). These results suggest that lithium administration may cause an initial alteration of the 5‐HT available for release at the nerve ending, which is followed after subsequent treatment by an increase in the rate of 5‐HT synthesis. The possible clinical significance of these findings is discussed.

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1. We have retrospectively analysed data collected by a local adverse drug reactions reporting scheme in an acute hospital medical setting and have determined the numbers and types of reactions that would have merited notification as yellow card reports according to the guidelines of the Committee on Safety of Medicines. 2. The data related to 20,695 consecutive acute general medical admissions on seven general medical wards (140 beds) and were collected over 3 years, from April 1990 to March 1993. 3. Over 3 years there were 1420 reports of suspected adverse drug reactions, a rate of 68.7 per 1000 admissions. 4. If the guidelines for reporting issued by the Committee on Safety of Medicines had been strictly followed, 477 yellow cards would have been sent (23.1 per 1000 admissions). In 357 of these reports (74.8%), the reaction had caused admission to hospital. Only 31 of the 477 potential cards (6.5%) involved black triangle drugs and 10 of these were for minor reactions. 5. Only 30 of the 477 potential yellow cards (6.3%) were known to have been sent. The majority of those reactions not reported were for drug-related admissions, most of which were for well-known reactions to established drugs. 6. We have confirmed and quantified the extent of under-reporting of serious suspected adverse drug reactions to the Committee on Safety of Medicines from our hospital medical unit.