Uptake of serotonin into rat platelets and synaptosomes: comparative structure-activity relationships, energetics and evaluation of the effects of acute and chronic nortriptyline administration.

In order to establish whether the uptake systems in platelets and synaptosomes are equivalent, the structure-activity relationships for drug-induced inhibition of serotonin uptake were examined in vitro. The rank order for potency of inhibitors was the same in platelets as in synaptosomes, namely imipramine greater than nortriptyline greater than desmethylimipramine much much greater than norepinephrine greater than histamine; in addition, serotonin uptake was clearly distinguishable from the norepinephrine synaptic uptake mechanism, which displayed a different rank order. The synaptosomal uptake of serotonin was, however, much more dependent upon maintenance of Na+-K+-ATPase activity for its energy source than was the platelet uptake mechanism. Acute administration of nortriptyline produced substantial inhibition of platelet serotonin uptake and a smaller degree of inhibition of synaptosomal uptake; inhibition was detectable even after extensive washing of the platelet and synaptosome preparations, and was associated with persistent binding of the drug to the organelles. Chronic infusion of nortriptyline (20 mg/kg for 21 days, followed by a 24 hr washout period to dissipate persistent binding) did not alter the uptake capacity of synaptosomal or platelet preparations, but did cause a shift in the drug specificity of inhibitors. The latter effect was in opposite directions in platelets vs. synaptosomes. These data indicate that the platelet uptake mechanism does bear some resemblance to that seen in serotonergic neurons, but that the energy source for transport differs and the two mechanisms respond differently to prolonged drug administration in vivo. The use of uptake as a marker during the course of antidepressant administration is likely to be confounded by persistent direct drug effects on these organelles.

Duke Scholars

Author Theodore Alan Slotkin Pharmacology & Cancer Biology