Discriminative stimulus properties of fenfluramine: evidence for serotonergic involvement

Rats were trained to discriminate 3 mg/kg fenfluramine (FEN) from saline using a milk-reinforced (FR 10 schedule) two-lever operant task. To assess the involvement of the serotonin (5-HT) system in elicitation of the FEN cue, 5-HT compounds were tested for their ability to substitute for or to antagonize the the discriminative stimulus produced by FEN. Following acquisition, the FEN cue was dose-dependent, had a rapid onset (10 min) and a long duration (12 h), and was stereospecific. The putative 5-HT receptor antagonists methysergide and cinanserin antagonized the FEN discriminative stimulus, while chlordiazepoxide, an indirect inhibitor of 5-HT turnover, did not. The FEN cue was also antagonized by the selective 5-HT reuptake inhibitor fluoxetine. Norfenfluramine, p-fluoro-amphetamine, and p-chloroamphetamine, compounds structurally and pharmacologically similar to FEN, substituted for FEN, whereas fluoxetine, cinanserin, methysergide, and chlordiazepoxide did not. The 5-HT precursor 5-hydroxytryptophan partially generalized to the FEN cue. It was further shown that the discriminative stimulus properties of FEN are not based on its anorectic action. These results suggest that the cue properties of FEN might be partially mediated through an interaction with the 5-HT system.