Evaluation of chemically diverse 5-H[T.sub.2C] receptor agonists on behaviours motivated by food and nicotine and on side effect profiles

• Published in: Psychopharmacology 2013-04, Vol.226 (3), p.475
• Main Authors: Higgins, G.A, Silenieks, L.B, Lau, W, de Lannoy, I.A.M, Lee, D.K.H, Izhakova, J, Coen, K, Le, A.D, Fletcher, P.J
• Format: Article
• Language: English
• Subjects: Addiction; Analysis; Care and treatment; Complications and side effects; Dosage and administration; Lorcaserin; Obesity; Pharmacokinetics
• ISSN: 0033-3158
• DOI: 10.1007/s00213-012-2919-2

Rationale Selective 5-H[T.sub.2C] receptor agonists, such as lorcaserin, are being developed for the treatment of obesity. Studies suggest that they may also have therapeutic potential for addictive behaviours including nicotine dependence, although few drugs of this class have been evaluated. Objectives The primary aim was to evaluate the highly selective 5-H[T.sub.2C] agonist, CP-809101, against food-motivated (operant FR5 and progressive ratio schedules, palatability-induced feeding) and nicotine-motivated (intravenous self-administration, drug discrimination) behaviours in rats and to compare with equivalent findings for the structurally distinct 5-H[T.sub.2C] receptor agonists lorcaserin and Ro 60-0175. The secondary aims were to evaluate the side effect profiles of lorcaserin and CP-809101 and to determine the plasma levels of lorcaserin at a dose (1 mg/kg) that reduces both food and nicotine reinforcement for comparison to plasma concentrations reported in human trials. Results CP-809101 (0.3-3 mg/kg SC) reduced responding for both nicotine and food and blocked the discriminative stimulus properties of nicotine in a similar manner to lorcaserin and Ro 60-0175. Behaviours such as hypolocomotion, chewing and ptosis became evident following both CP809101 and lorcaserin administration at higher doses. Plasma levels of lorcaserin were of similar range to those reported in obesity trials. Conclusions These studies support the utility of 5-H[T.sub.2C] agonists as a therapeutic approach to treat nicotine dependence. Plasma exposure levels after acute lorcaserin treatment suggest that equivalent dosages could be used to evaluate these drugs in obesity and smoking cessation trials. Finally, there may be differences in the side effect profiles between lorcaserin and CP-809101, raising the possibility for tolerability differences amongst 5-H[T.sub.2C] agonists. Keywords Functional selectivity * Nicotine self-administration * Nausea * 5-H[T.sub.2C] agonist * Lorcaserin * CP-809101 Ro 60-0175 * Pharmacokinetics * Rat