In rats, reserpine depleted brain serotonin (5-HT) by 86% but did not block the behavioral syndrome caused by p-chloroamphetamine (PCA) or 5-MeODMT, except for changes in Straub tail and head weaving. Extracellular serotonin in the frontal cortex was about 1/1000th of brain levels before PCA, and PCA increased dialysate serotonin similarly in reserpine- and vehicle-pretreated rats. The results suggest PCA releases serotonin from the neuronal cytoplasm to produce the syndrome, while normal physiological release comes from vesicular stores.
Analgesia caused by a brief footshock in rats is reduced by drugs that increase serotonin (5-HT) activity—fenfluramine, which releases serotonin, and 5-MeODMT, a fast-acting serotonin agonist. These reductions are blocked by serotonin antagonists cyproheptadine and methiothepin, but those antagonists alone do not affect the shock-induced pain relief. Thus, the natural analgesia from brief footshock likely does not rely on serotonin mechanisms, though it can be altered by pharmacologically boosting serotonin. 5-MeODMT could also weaken analgesia after it starts, possibly by disrupting memory rather than pain processing directly.