The concentration of 5-HT in the rat brain displays a marked 24-hour variation which is 180° out of phase with that observed for total brain TRY levels. This investigation was undertaken to study the factors which might prove responsible for this difference. Previous experiments showed 5-HIAA levels were purely a reflection of 5-HT concentrations i.e. the latter were not low in the dark phase because turnover was high. TRY in the plasma has the unusual property of binding to albumin and it is the 'free' fraction which is functionally important. A comparison was made of 'free' and total TRY levels in the brain as TRY hydroxylase is unsaturated with substrate and fluctuations in the functional TRY pool may be important in controlling 5-HT levels. A 24-hour variation in 'free' TRY was found, again there was a 180° phase difference with the 5-HT rhythm. The activity of the two synthetic enzymes TRY hydroxylase and 5-HTP decarboxylase were measured by in vitro methods (radiometric and fluorimetric, respectively). No significant 24-hour variation in enzyme activity was evident, suggesting no regulation by synthesis rate. In vivo studies followed in which a behavioural model of induced hyperactivity, thought to reflect central serotonergic activity, showed a 24-hour variation in hyperactivity, the peak level occurring in the latter part of the light period. The effect of re-uptake blockade on this syndrome indicated a reduced rate of re-uptake coinciding with increased hyperactivity rather than an increased rate of 5-HT release. In the light of these results, the possibility is considered that regulation of 5-HT levels is not via synthesis but that 5-HT is produced in excess and that functional control may be brought about by intraneuronal binding and metabolism.
|Date of Award||1979|