Norfenfluramine, the fenfluramine metabolite, provides stimulus control: evidence for serotonergic mediation

Nine male rats were trained to discriminate 1.4 mg/kg norfenfluramine (NF) from its vehicle using a two-lever, food-motivated, operant discrimination task. Once trained, the rats showed a dose-dependent decrease in responding on the NF-correct lever following decreased doses of NF (ED50 = 0.71 mg/kg). Administration of 2.0 mg/kg fenfluramine (FEN) produced 100% responding on the NF-correct lever and decreasing doses of FEN, likewise, produced a dose-dependent decrease in responding on the NF-correct lever (ED50 = 1.30 mg/kg). Time-course data indicated that NF has a fast onset and a peak effect at 20-60 min after administration. Analysis of the time-course data provided a half-life of approximately 8 hr. In contrast, FEN did not show the rapid onset that was observed with NF. However, NF had a similar peak effect and half-life. These results indicate a pharmacological similarity between NF and FEN. However, the difference in onset of action suggests a possible difference between the parent drug and its metabolite. The serotonergic agonists mCPP, DOI, 5-MeODMT and LSD generalized to 1.4 mg/kg NF, whereas neither TFMPP nor 8-OHDPAT generalized to NF. The dopaminergic agonist AMPH also did not generalize to NF. The implications of these findings are discussed.