Characterization of the discriminative stimulus effects of lorcaserin in rats

Abstract

Lorcaserin is approved by the Food and Drug Administration for treating obesity and is under consideration for treating substance use disorders; it has agonist properties at serotonin (5-HT)2C receptors and might also have agonist properties at other 5-HT receptor subtypes. This study used drug discrimination to investigate the mechanism(s) of action of lorcaserin. Male Sprague-Dawley rats discriminated 0.56 mg/kg i.p. lorcaserin from saline while responding under a fixed-ratio 5 schedule for food. Lorcaserin (0.178–1.0 mg/kg) dose-dependently increased lorcaserin-lever responding. The 5-HT2C receptor agonist mCPP and the 5-HT2A receptor agonist DOM each occasioned greater than 90% lorcaserin-lever responding in seven of eight rats. The 5-HT1A receptor agonist 8-OH-DPAT occasioned greater than 90% lorcaserin-lever responding in four of seven rats. The 5-HT2C receptor selective antagonist SB 242084 attenuated lorcaserin-lever responding in all eight rats and the 5-HT2A receptor selective antagonist MDL 100907 attenuated lorcaserin-lever responding in six of seven rats. These results suggest that, in addition to agonist properties at 5-HT2C receptors, lorcaserin also has agonist properties at 5-HT2A and 5-HT1A receptors. Because some drugs with 5-HT2A receptor agonist properties are abused, it is important to fully understand the behavioral effects of lorcaserin while considering its potential for treating substance use disorders.

Inhibition of Cocaine and 3,4-Methylenedioxypyrovalerone (MDPV) Self-Administration by Lorcaserin Is Mediated by 5-HT2C Receptors in Rats

“…Although the capacity of a 5-HT 2C receptor antagonist (SB242084) to at least partially inhibit the effects of lorcaserin on drug self-administration ( Higgins et al, 2012 ; Harvey-Lewis et al, 2016 ; Neelakantan et al, 2017 ) suggests that these effects are mediated by the 5-HT 2C receptor, the single-dose design of these experiments did not allow for the nature of the antagonist effects to be characterized (e.g., competitive and surmountable, irreversible, etc.). It is also important to note that these studies reported decreases in drug self-administration at doses of lorcaserin (∼0.6–1 mg/kg) that are ∼20- to 30-fold larger than those required to induce yawning, a 5-HT 2C receptor-mediated effect, and comparable to those that have been shown to produce 5-HT 2A receptor-mediated effects in rats ( Serafine et al, 2015 , 2016 ). Moreover, because previous studies have examined only the interactions between lorcaserin and 5-HT 2C antagonists, it is currently unclear whether the actions of lorcaserin at other 5-HT receptors (e.g., 5-HT 2A and 5-HT 1A receptors) also contribute to the capacity of lorcaserin to decrease the reinforcing effects of stimulant drugs.…”

“…Preclinical studies demonstrating that lorcaserin can decrease the ongoing self-administration of drugs with diverse mechanisms of action (e.g., nicotine, alcohol, cocaine, methamphetamine, and oxycodone) suggest that lorcaserin might also have utility as a pharmacotherapy for addiction. Although studies with 5-HT 2C receptor antagonists ( Higgins et al, 2012 ; Harvey-Lewis et al, 2016 ; Neelakantan et al, 2017 ) suggest that the capacity of lorcaserin to decrease drug self-administration is mediated by 5-HT 2C receptors, the doses of lorcaserin typically required to decrease drug self-administration are ∼20- to 30-fold larger than those required to induce 5-HT 2C receptor-mediated behavioral effects (e.g., yawning) and are comparable to those that produce 5-HT 2A receptor-mediated behavioral effects ( Serafine et al, 2015 , 2016 ) and to decrease responding for food ( Higgins et al, 2012 ; Briggs et al, 2016 ; Collins et al, 2016b ), raising the possibility that other 5-HT receptor subtypes are also contributing to the effectiveness of lorcaserin to decrease drug self-administration. Accordingly, the current study sought to characterize the relative contribution of actions at 5-HT 2C , 5-HT 2A , and 5-HT 1A receptors to the effectiveness of lorcaserin to decrease stimulant self-administration.…”

“…Nevertheless, the inability of MDL100907 to alter the effects of lorcaserin does not mean that lorcaserin is devoid of agonist actions at the 5-HT 2A receptor. In addition to evidence linking the doses used in these studies to 5-HT 2A receptor-mediated effects in rats ( Serafine et al, 2015 , 2016 ), doses of lorcaserin only slightly larger than the maximum approved dose for use in humans (10 mg twice daily) have been reported to increase ratings of “high” and “bad” effects and to induce perceptual effects (e.g., hallucination) and other adverse effects (e.g., nausea, headache, dizziness, euphoric mood, etc.) in a sample of recreational polydrug abusers ( Shram et al, 2011 ).…”

Effects of lorcaserin (Belviq®) on nicotine- and food-maintained responding in non-human primates

“…It is of note, however, that lorcaserin also has activity at other 5-HT receptors. In this regard, a recent drug discrimination study found that the 5-HT 1A agonist, 8-OH-DPAT, and the selective 5-HT 2A agonist, DOM, engendered lorcaserin-like responding in rats trained to discriminate lorcaserin suggesting a role of 5-HT 1A and 5-HT 2A receptors in the behavioral effects of lorcaserin (Serafine et al, 2016). These results suggest that the role of various 5-HT receptor subtypes in lorcaserin’s therapeutic effects require further examination and highlight the importance of receptor-subtype selective pharmacological manipulations that might lead to medications with better safety and selectivity.…”

Lorcaserin Alters Serotonin and Noradrenaline Tissue Content and Their Interaction With Dopamine in the Rat Brain

“…Notwithstanding, its better pharmacological profile toward 5-HT 2C Rs, the differences between 0.3 and 3 mg/kg lorcaserin could also imply the recruitment of additional sites. Lorcaserin displays a higher affinity for 5-HT 2C Rs (Ki = 15 nM) compared to 5-HT 2A Rs (112 nM) and 5-HT 2B Rs (174 nM, acting as an antagonist) ( Thomsen et al, 2008 ), but previous data have reported that lorcaserin could recruit 5-HT 1A/2A Rs in behavioral responses such as forepaw treading and drug discrimination ( Serafine et al, 2015 ; Serafine et al, 2016 ). A brief behavioral evaluation of our rats receiving lorcaserin indicated that rats displayed purposeless oral movements at the low dose, as expected from the 5-HT 2C Rs agonist profile ( Gong et al, 1992 ; Lagiere et al, 2013 ; Navailles et al, 2013b ; Kreiss and De Deurwaerdere, 2017 ).…”