Role of serotonin 5HT_2Creceptors in the discriminative stimulus properties of lorcaserin in male C57BL/6 mice

The serotonin 2C receptor (5-HT_2C) has been investigated as a potential therapeutic target for a variety of psychiatric disorders, as well as the treatment of obesity. A stumbling block in the development of these medications is identifying agonists with selectivity for 5-HT_2C over 5-HT_2A and 5-HT_2B. Lorcaserin (Belviq) is a serotonin 5-HT_2C agonist that was previously marketed as a weight-loss medication but was voluntarily withdrawn from the market because of a small, but an increased risk of serious side effects. The present study examined the discriminative stimulus properties of 2.0 mg/kg lorcaserin in a two-lever drug discrimination assay in male C57BL/6 mice using a fixed ratio 12 reinforcement schedule. A generalization curve with lorcaserin yielded an effective dose₅₀ (ED₅₀) = 0.56 mg/kg for infstitution for the training dose. Lorcaserin produced a rapid onset, but short-acting (∼60 min), discriminative stimulus, as full generalization was found as early as 15 min after drug administration. The 5-HT_2C agonist meta-chlorophenylpiperazine fully infstituted for lorcaserin with an ED₅₀ = 0.31 mg/kg, and the 5-HT_2C antagonist SB 242084 significantly blocked lorcaserin-lever responding (maximal effect at 0.25 mg/kg dose). Conversely, the 5-HT_1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin did not infstitute for lorcaserin. Thus, lorcaserin's discriminative stimulus appears to be mediated by agonist activity at 5HT_2C receptors in C57BL/6 mice. These results demonstrated that lorcaserin drug discrimination can be trained in C57BL/6 mice and that it is a useful in-vivo assay for the future development of psychotherapeutic drugs for psychiatric disorders with selective 5-HT_2C agonist activity.