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

• Published in: Neuropharmacology 2011-09, Vol.61 (3), p.513
• Main Authors: Cunningham, Kathryn A, Fox, Robert G, Anastasio, Noelle C, Bubar, Marcy J, Stutz, Sonja J, Moeller, F Gerard, Gilbertson, Scott R, Rosenzweig-Lipson, Sharon
• Format: Article
• Language: English
• Subjects: Animals; Azepines - administration & dosage; Azepines - therapeutic use; Behavior, Animal - drug effects; Cocaine - administration & dosage; Cocaine - toxicity; Cocaine-Related Disorders - drug therapy; Cues; Dietary Sucrose - administration & dosage; Dopamine Uptake Inhibitors - administration & dosage; Dopamine Uptake Inhibitors - toxicity; Dose-Response Relationship, Drug; Feeding Behavior - drug effects; Impulsive Behavior - drug therapy; Indoles - administration & dosage; Indoles - therapeutic use; Male; Motor Activity - drug effects; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C - chemistry; Reward; Self Administration; Serotonin 5-HT2 Receptor Agonists - administration & dosage; Serotonin 5-HT2 Receptor Agonists - therapeutic use; Serotonin 5-HT2 Receptor Antagonists - therapeutic use
• ISSN: 1873-7064
• DOI: 10.1016/j.neuropharm.2011.04.034

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.