title: Evaluation of chemically diverse 5-HT₂c receptor agonists on behaviours motivated by food and nicotine and on side effect profiles.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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 CP-809101 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-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.
authors.affiliation: InterVivo Solutions Inc, 120 Carlton St., Toronto, ON M5A 4K2, Canada. guyh@intervivo.com
authors.forename: G A
authors.initials: GA
authors.lastname: Higgins
authors.forename: L B
authors.initials: LB
authors.lastname: Silenieks
authors.forename: W
authors.initials: W
authors.lastname: Lau
authors.forename: I A M
authors.initials: IA
authors.lastname: de Lannoy
authors.forename: D K H
authors.initials: DK
authors.lastname: Lee
authors.forename: J
authors.initials: J
authors.lastname: Izhakova
authors.forename: K
authors.initials: K
authors.lastname: Coen
authors.forename: A D
authors.initials: AD
authors.lastname: Le
authors.forename: P J
authors.initials: PJ
authors.lastname: Fletcher
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005021:Ethylamines / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D005247:Feeding Behavior; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D009042:Motivation; D009538:Nicotine / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects / Q000378:metabolism; D012055:Reinforcement Schedule; D012646:Self Administration; D058826:Serotonin 5-HT2 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D001552:Benzazepines; C518685:CP-809,101; D005021:Ethylamines; D007211:Indoles; D010879:Piperazines; D011719:Pyrazines; D044405:Receptor, Serotonin, 5-HT2C; C103848:Ro 60-0175; D058826:Serotonin 5-HT2 Receptor Agonists; C506658:lorcaserin; D009538:Nicotine