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

Serotonin (5-HT) controls affective and motivational aspects of palatable food and drug reward and the 5-HT_2C receptor (5-HT_2CR) has emerged as a key regulator in this regard. We have evaluated the efficacy of a selective 5-HT_2CR 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 (ID₅₀ = 1.19 mg/kg) and sucrose (ID₅₀ = 0.7 mg/kg) as well as reinstatement (ID₅₀ = 0.5 mg/kg) elicited by exposure to cocaine-associated contextual cues, but not sucrose-associated contextual cues. The ID₅₀ 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 (ID₅₀ = 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 _2CR 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_2CR 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_2CR agonists as adjunctive therapy in chronic health maladies including obesity, eating disorders and drug addiction.