Evaluation of lorcaserin as an anticonvulsant in juvenile Fmr1 knockout mice

Abstract

Recent preclinical and clinical studies suggest that lorcaserin, a preferential serotonin 2C receptor (5-HT_2CR) agonist that was approved for the treatment of obesity, possesses antiepileptic properties. Here, we tested whether lorcaserin (1, 3, 5.6, 10 mg/kg) is prophylactic against audiogenic seizures (AGSs) in juvenile Fmr1 knockout mice, a mouse model of fragile X syndrome (FXS). MPEP (30 mg/kg), a non-competitive mGluR5 receptor antagonist, was used as a positive control. As lorcaserin likely engages 5-HT_2ARs at therapeutic doses, we pretreated one group of mice with the selective 5-HT_2AR antagonist/inverse agonist, M100907 (0.03 mg/kg), alone or before administering lorcaserin (5.6 mg/kg), to discern putative contributions of 5-HT_2ARs to AGSs. We also assessed lorcaserin's in vitro pharmacology at human (h) and mouse (m) 5-HT_2CRs and 5-HT_2ARs and its in vivo interactions at m5-HT_2CRs and m5-HT_2ARs. MPEP significantly decreased AGS prevalence (P = 0.011) and lethality (P = 0.038). Lorcaserin, 3 mg/kg, attenuated AGS prevalence and lethality by 14 % and 32 %, respectively, however, results were not statistically significant (P = 0.5 and P = 0.06); other doses and M100907 alone or with lorcaserin also did not significantly affect AGSs. Lorcaserin exhibited full efficacy agonist activity at h5-HT_2CRs and m5-HT_2CRs, and near full efficacy agonist activity at h5-HT_2ARs and m5-HT_2ARs; selectivity for activation of 5-HT_2CRs over 5-HT_2ARs was greater for human (38-fold) compared to mouse (13-fold) receptors. Lorcaserin displayed relatively low affinities at antagonist-labeled 5-HT_2CRs and 5-HT_2ARs, regardless of species. Lorcaserin (3 and 5.6 mg/kg) increased the 5-HT_2AR-dependent head-twitch response (HTR) elicited by (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) in mice (P = 0.03 and P = 0.02). At 3 mg/kg, lorcaserin alone did not elicit an HTR. If mice were treated with the selective 5-HT_2CR antagonist SB 242084 (0.5 or 1 mg/kg) plus lorcaserin (3 mg/kg), a significantly increased HTR was observed, relative to vehicle (P = 0.01 and P = 0.03), however, the HTR was much lower than what was elicited by DOI or DOI plus lorcaserin. Lorcaserin, 3 mg/kg, significantly reduced locomotor activity on its own, an effect reversed by SB 242084, and lorcaserin also dose-dependently reduced locomotor activity when administered prior to DOI (Ps<0.002). These data suggest that lorcaserin may engage 5-HT_2CRs as well as 5-HT_2ARs in mice at doses as low as 3 mg/kg. The similar activity at m5-HT_2CRs and m5-HT_2ARs suggests careful dosing of lorcaserin is necessary to selectively engage 5-HT_2CRs in vivo. In conclusion, lorcaserin was ineffective at preventing AGSs in Fmr1 knockout mice. Lorcaserin may not be a suitable pharmacotherapy for seizures in FXS.

Keywords: 5-HT(2A); 5-HT(2C); Audiogenic seizures; Fmr1 knockout mouse; Head-twitch response; Lorcaserin.