Destroying serotonin-producing neurons in the brain with a chemical (5,7-DHT) made rats more sensitive to a drug that activates serotonin receptors (5-MeO-DMT). The stronger behavioral response matched how much serotonin was lost. But the same treatment did not increase the hyperactivity caused by a different drug (RU-24969) that targets a specific serotonin receptor subtype (5HT1). This suggests that different serotonin receptors control different behaviors and that losing serotonin neurons changes sensitivity to some, but not all, receptor-activating drugs.
In male mice, the head twitch response caused by two different drugs that affect serotonin (5-HT) shows a daily rhythm. Depleting brain serotonin with PCPA increased the response to the direct serotonin receptor agonist 5-MeODMT on days 3 and 5, when serotonin levels were low, but not on day 12 when levels had recovered. PCPA reduced the response to PCA, which releases serotonin from neurons. Under a 12-hour light-dark cycle, the response to the direct agonist peaked near the end of the dark period when serotonin was lowest, while the response to the serotonin-releasing drug peaked in the middle of the light period when serotonin was highest.