The 24 hour variations in plasma total and free tryptophan, brain tryptophan, brain 5-hydroxytryptamine (5HT) and brain 5-hydroxyindoleacetic acid (5HIAA) concentrations have been examined. The 24 hour variation in synaptosomal uptake of tryptophan and 5-hydroxytryptamine has also been studied. Maximum concentrations of plasma total and free tryptophan, brain 5HIAA levels and synaptosomal uptake of tryptophan and 5HT were found to be at 07.00 hours. Brain 5HT concentrations were highest 13.00 hours and brain tryptophan at 19.00 hours. The effect of two days or 14 days administration of imipramine, clomipramine and zimelidine in the drinking water on these rhythms was determined. The effect of these drugs on the circadian variation in body temperature and the free-running circadian rhythm in locomotor activity was also determined. Acute administration of imipramine abolished the circadian variation in plasma and brain concentrations of TRY and SEIAA, but not of 5HT. Chronic administration did riot do this, but the phase of the rhythms was altered. The 'rhythm' in brain TRY levels was abolished by chronic imipramine and the levels reduced. Uptake kinetics were also reduced and phase shifted by chronic treatment. Clomipramine, when administered for two days was generally without effect; 5HT turnover was increased and the phase of the 5HIAA concentration rhythm advanced or abolished (high dose only). Brain TRY levels were reduced by chronic treatment and the rhythm abolished. The rhythm in 5HTAA levels was also abolished. Uptake kinetics were phase shifted and reduced. Rhythms were not abolished by zimelidine, but rhythm characteristics were altered. Brain TRY was reduced, as was its uptake into synaptosomes. 5HT levels were unaffected but turnover was reduced by chronic treatment with a high dose. The rhythm in 5HIAA levels was phase advanced. Each drug reduced the amplitude of the temperature rhythm by increasing the value of the minimum temperature, which was in the middle of the light phase. The period of the circadian free-running activity rhythm was initially lengthened. However, this subsequently became disrupted (after about seven days) and later revealed a rhythm in activity with a very short period, such that several cycles occurred within 24 hours. It is proposed that these drugs exert some of their antidepressant action by modifying circadian rhythms in 5HT metabolism, and that 5HT metabolism and function may be controlled in part by uptake of TRY across the BBB and nerve ending membrane.
|Date of Award||1982|