title: Selective serotonin 5-HT(2C) receptor activation suppresses the reinforcing efficacy of cocaine and sucrose but differentially affects the incentive-salience value of cocaine- vs. sucrose-associated cues.
abstract: Serotonin (5-HT) controls affective and motivational aspects of palatable food and drug reward and the 5-HT(2C) receptor (5-HT(2C)R) has emerged as a key regulator in this regard. We have evaluated the efficacy of a selective 5-HT(2C)R agonist, WAY 163909, in cocaine and sucrose self-administration and reinstatement assays employing parallel experimental designs in free-fed rats. WAY 163909 dose-dependently reduced the reinforcing efficacy of cocaine (ID(50) = 1.19 mg/kg) and sucrose (ID(50) = 0.7 mg/kg) as well as reinstatement (ID(50) = 0.5 mg/kg) elicited by exposure to cocaine-associated contextual cues, but not sucrose-associated contextual cues. The ID(50) of WAY 163909 predicted to decrease the reinforcing efficacy of cocaine or sucrose as well as reinstatement upon exposure to cocaine-associated cues was ∼5-12-fold lower than that predicted to suppress horizontal ambulation (ID(50) = 5.89 mg/kg) and ∼2-5-fold lower than that predicted to suppress vertical activity (ID(50) = 2.3 mg/kg). Thus, selective stimulation of the 5-HT(2C)R decreases the reinforcing efficacy of cocaine and sucrose in freely-fed rats, but differentially alters the incentive-salience value of cocaine- vs. sucrose-associated cues at doses that do not impair locomotor activity. Future research is needed to tease apart the precise contribution of 5-HT(2C)R neurocircuitry in reward and motivation and the learning and memory processes that carry the encoding for associations between environmental cues and consumption of rewarding stimuli. A more complete preclinical evaluation of these questions will ultimately allow educated proof-of-concept trials to test the efficacy of selective 5-HT(2C)R agonists as adjunctive therapy in chronic health maladies including obesity, eating disorders and drug addiction.
authors.affiliation: Center for Addiction Research, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77550-0615, USA. kcunning@utmb.edu
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Cunningham
authors.forename: Robert G
authors.initials: RG
authors.lastname: Fox
authors.forename: Noelle C
authors.initials: NC
authors.lastname: Anastasio
authors.forename: Marcy J
authors.initials: MJ
authors.lastname: Bubar
authors.forename: Sonja J
authors.initials: SJ
authors.lastname: Stutz
authors.forename: F Gerard
authors.initials: FG
authors.lastname: Moeller
authors.forename: Scott R
authors.initials: SR
authors.lastname: Gilbertson
authors.forename: Sharon
authors.initials: S
authors.lastname: Rosenzweig-Lipson
mesh_terms: D000818:Animals; D001381:Azepines / Q000008:administration & dosage / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage* / Q000633:toxicity; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D003463:Cues; D019422:Dietary Sucrose / Q000008:administration & dosage*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005247:Feeding Behavior / Q000187:drug effects*; D007175:Impulsive Behavior / Q000188:drug therapy; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000737:chemistry*; D012201:Reward; D012646:Self Administration; D058826:Serotonin 5-HT2 Receptor Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000627:therapeutic use
chemical_list: C501656:1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta(b)(1,4)diazepino(6,7,1hj)indole; D001381:Azepines; D019422:Dietary Sucrose; D018765:Dopamine Uptake Inhibitors; D007211:Indoles; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D003042:Cocaine