Discriminative stimulus properties of (±)-fenfluramine: The role of 5-HT₂ receptor subtypes

The role of serotonin 5-HT₂ receptors (5-HT₂R) in the discriminative stimulus effects of fenfluramine was investigated. Male Sprague-Dawley rats were trained to discriminate (±)-fenfluramine (2 mg/kg ip) from saline using a 2-lever, water-reinforced paradigm. Drug-lever responding after fenfluramine was dose-dependent. The 5-HT_2C/1B agonist mCPP and the 5-HT_2CR agonist MK 212 fully substituted, whereas the 5-HT_2A/2CR agonist DOI partially substituted, for the training drug. The 5-HT_2BR agonist BW 723C86 engendered saline-lever responding. The 5-HT_2C/2BR antagonist SB 206553 completely antagonized the fenfluramine discrimination as well as the full substitutions of mCPP and MK 212 and the partial substitution of DOI. The selective 5-HT₂AR antagonist M100907 partially suppressed the stimulus effects of fenfluramine, mCPP, and MK 212 and almost fully attenuated the partial substitution of DOI. RS 102221, a selective 5-HT_2CR antagonist that does not cross the blood-brain barrier, did not alter the fenfluramine cue. Results demonstrate that the discriminative stimulus effects of fenfluramine are centrally mediated by 5-HT_2CR and to some extent by 5-HT_2AR.