Characterization of the discriminative stimulus effects of lorcaserin in rats

Several decades of preclinical research suggest that drugs with agonist effects at serotonin (5‐HT) 2C receptors might be useful for treating substance use disorders. Lorcaserin, a drug currently used to treat obesity and under consideration for treating substance use disorders, has agonist properties at 5‐HT 2C receptors; however, recent evidence suggests that it might also have agonist effects at other 5‐HT receptor subtypes. The present experiment used drug discrimination, a procedure that is highly pharmacologically selective, to further investigate the mechanism(s) of action of lorcaserin. Male Sprague‐Dawley rats (n=7) discriminated 0.56 mg/kg i.p. lorcaserin from saline while responding under a fixed ratio 5 schedule of food presentation. Lorcaserin (0.178–1.0 mg/kg) dose‐dependently increased lorcaserin‐lever responding. Several direct‐acting 5‐HT receptor agonists and antagonists were examined alone and in combination with lorcaserin. The 5‐HT 2C receptor agonist mCPP occasioned greater than 90% lorcaserin‐lever responding in 6/7 rats, as did the 5‐HT 2A receptor agonist DOM. The 5‐HT 1A receptor agonist 8‐OH‐DPAT occasioned greater than 90% lorcaserin‐lever responding in only 4/7 rats. The 5‐HT 2C receptor selective antagonist SB 242084 attenuated lorcaserin‐lever responding in all 7 rats. In contrast, the 5‐HT 2A receptor selective antagonist MDL 100907 attenuated lorcaserin‐lever responding in 5/7 rats. In addition to producing directly observable behavior consistent with agonist properties at 5‐HT 2C receptors (i.e. yawning), at large doses lorcaserin also induces behavioral effects that are consistent with agonist properties at 5‐HT 1A receptors (i.e., forepaw treading). Moreover, when examined in combination with a selective 5‐HT 2C receptor antagonist lorcaserin also induced behavior consistent with agonist properties at 5‐HT 2A receptors (i.e., head twitching). Taken together, these results suggest that in addition to agonist effects at 5‐HT 2C receptors, lorcaserin also has agonist effects at 5‐HT 2A and 5‐HT 1A receptors. Given that 5‐HT 2A receptor agonists can be abused (e.g., LSD) it is crucial to fully understand the behavioral effects of lorcaserin if it is to be considered a potential pharmacotherapy for substance use disorders. Support or Funding Information Supported by NIH Grants K05 DA017918 and T32 DA031115.