Vesicular and juxtavesicular serotonin: effects of lysergic acid diethylamide and reserpine.

An extensive analysis of subcellular serotonin (5-HT) compartmentation with and without reserpine was undertaken in order to localize further the effect of LSD on rat brain 5-HT. Modification of the subfractionation procedure resulted in an increase in purity of fractions and a decrease in variability of 5-HT content. With the modified procedure, the administration of LSD produced a significant increase in 5-HT in the nerve-ending fraction prepared from rat whole brain. LSD caused a 50% increase in 5-HT in the vesicular fraction which was recovered after osmotic disruption of nerve-endings. The increase of 5-HT in the vesicular fraction after LSD was not demonstrable in rats treated with reserpine for as long as 2 weeks postreserpine. Instead, with reserpine pretreatment the LSD-induced increase in 5-HT was localized to the intrasynaptosomally derived "end supernatant" as early as 48 hours postreserpine. Thus, an unanticipated "juxtavesicular" site capable of 5-HT retention or binding was detected. In crude subcellular fractions, by contrast, significant increase in 5-HT were not observed with LSD administration until 4 days after reserpine, at which time at least a 50% 5-HT repletion had occurred. This study of drug interactions suggests a juxtavesicular compartment that may be of functional importance in presynaptic binding or transport of 5-HT.