Evaluation of chemically diverse 5-HT2C receptor agonists on behaviours motivated by food and nicotine and on side effect profiles
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Selective 5-HT2C 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.
The primary aim was to evaluate the highly selective 5-HT2C 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-HT2C 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.
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 CP-809101 and lorcaserin administration at higher doses. Plasma levels of lorcaserin were of similar range to those reported in obesity trials.
These studies support the utility of 5-HT2C 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-HT2C agonists.
KeywordsFunctional selectivity Nicotine self-administration Nausea 5-HT2C agonist Lorcaserin CP-809101 Ro 60–0175 Pharmacokinetics Rat
- Arena Pharmaceuticals (2010) Briefing document: NDA 22–529; lorcaserin hydrochloride (APD356)Google Scholar
- Higgins GA, Joharchi N, Sellers EM (1993) Behavioral effects of the 5-hydroxytryptamine3 receptor agonists 1-phenylbiguanide and m-chlorophenylbiguanide in rats. J Pharm Exp Ther 264:1440–1449Google Scholar
- Higgins GA, Silenieks LB, Roβmann A, Rizos Z, Noble K, Soko AD, Fletcher PJ (2012) The 5-HT2C receptor agonist lorcaserin reduces nicotine self-administration, discrimination and reinstatement: relationship to feeding behavior and impulse control. Neuropsychopharmacology 37:1177–1191PubMedCrossRefGoogle Scholar
- Kalgutkar AS, Dalvie DK, Aubrecht J, Smith EB, Coffing SL, Cheung JR, Vage C, Lame ME, Chiang P, McClure KF, Maurer TS, Coelho RV, Soliman VF, Schildknegt K (2007) Genotoxicity of 2-(3-chlorobenzyloxy)-6-(piperazinyl)pyrazine, a novel 5-hydroxytryptamine2C receptor agonist for the treatment of obesity: role of metabolic activation. Drug Metab Dispos 35:848–858PubMedCrossRefGoogle Scholar
- Moya PR, Berg KA, Gutierrez-Hernandez MA, Saez-Briones P, Reyes-Parada M, Cassels BK, Clarke WP (2007) Functional selectivity of hallucinogenic phenethylamine and phenylisopropylamine derivatives at human 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors. J Pharm Exp Ther 321:1054–1061CrossRefGoogle Scholar
- O’Connor EC, Parker D, Rollema H, Mead AN (2010) The alpha4beta2 nicotinic acetylcholine-receptor partial agonist varenicline inhibits both nicotine self-administration following repeated dosing and reinstatement of nicotine seeking in rats. Psychopharmacology 208:365–376PubMedCrossRefGoogle Scholar
- Rollema H, Chambers LK, Coe JW, Glowa J, Hurst RS, Lebel LA, Lu Y, Mansbach RS, Mather RJ, Rovetti CC, Sands SB, Schaeffer E, Schulz DW, Tingley FD III, Williams KE (2007a) Pharmacological profile of the α4β2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid. Neuropharmacology 52:985–994PubMedCrossRefGoogle Scholar
- Thomsen WJ, Grottick AJ, Menzaghi F, Reyes-Saldana H, Espita S, Yuskin D, Whelan K, Martin M, Morgan M, Chen W, Al-Shamma H, Smith B, Chalmers D, Behan D (2008) Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization. J Pharmacol Exp Ther 325:577–587PubMedCrossRefGoogle Scholar