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.

Copyright © 2011. Published by Elsevier Ltd.

Figures

Fig. 1. WAY 163909 evokes a dose-dependent suppression of horizontal ambulation and vertical activity

[A] The time course of horizontal ambulation is divided into 15 min time bins across the 60 min session; [A, Inset] the mean total horizontal ambulation (counts/60 min) (± SEM) is represented following administration of vehicle (saline; Veh) or WAY 163909 (WAY; 0.3, 1, 3 or 10 mg/kg, i.p.). [B] The time course of vertical activity is divided into 15 min time bins across the 60 min session; [B, Inset] the mean total vertical activity (counts/60 min) (± SEM) is represented following administration of vehicle (saline; Veh) or WAY 163909 (WAY; 0.3, 1, 3, or 10 mg/kg, i.p.). *p< 0.05 vs. Veh.

Fig. 2. WAY 163909 dose-dependently suppresses cocaine self-administration

[A] Mean responses (+/− SEM) on the active (black circles) or inactive lever (white circles), and total number of cocaine infusions (+/− SEM; gray circles) are presented for the acquisition phase of cocaine self-administration training under FR1 – FR5 schedules of reinforcement. Active lever responses resulted in the delivery of an intravenous cocaine infusion (0.25 mg/kg/0.1 ml infusion) and simultaneous presentation of the cocaine-paired cues. [B] Mean responses (+/− SEM) on the active (black bars) or inactive lever (white bars) or [C] mean total cocaine infusions (+/− SEM; gray bars) following pretreatment with vehicle (saline; Veh) or WAY 163909 (0.5, 1 or 2 mg/kg, i.p., 15 min) (left panel) or following pretreatment with the 5-HT2CR antagonist SB 242084 (0.5 mg/kg, i.p., 15 min) plus vehicle (saline; Veh) or WAY 163909 (2 mg/kg, i.p.) (right panel) during the cocaine self-administration maintenance phase. Active lever responses resulted in the delivery of an intravenous cocaine infusion (0.25 mg/kg/0.1 ml infusion) according to an FR 5 schedule and simultaneous presentation of cocaine-paired cues. *p < 0.05 vs. Veh; ^p < 0.05 vs. WAY 163909 (2 mg/kg).

Fig. 3. WAY 163909 dose-dependently suppresses cocaine cue-evoked reinstatement

[A] Mean responses (+/− SEM) on the active (black circles) or inactive lever (white circles), and the total number of cocaine infusions (+/− SEM; gray circles) are presented for the acquisition phase of cocaine self-administration training under FR1 – FR5 schedules of reinforcement. Active lever responses resulted in the delivery of an intravenous cocaine infusion (0.75 mg/kg/0.1 ml infusion) and simultaneous presentation of the cocaine-paired cues. [B] Mean (+/− SEM) total number of responses on the active (black bars) or inactive lever (white bars) following extinction (“Extinction Baseline”) and upon pretreatment with vehicle (saline; Veh) or WAY 163909 (0.5, 1, or 1.5 mg/kg, i.p.) on the test day for reinstatement of extinguished cocaine-seeking behavior. Reinstatement was initiated by a single non-contingent presentation of cocaine-paired cues (pump and stimulus light). Each active lever press resulted in the presentation of the conditioned stimuli in the absence of cocaine delivery. *p < 0.05 vs. Extinction; ^p < 0.05 vs. Veh.

Fig. 4. WAY 163909 dose-dependently suppresses sucrose self-administration

[A] Mean responses (+/− SEM) on the active (black circles) or inactive lever (white circles), and total number of sucrose pellets (+/− SEM; gray circles) are presented for the acquisition phase of cocaine self-administration training under FR1 – FR5 schedules of reinforcement. Active lever responses resulted in the delivery of a single sucrose pellet (45 mg) and simultaneous presentation of the sucrose-paired cues. [B] Mean responses (+/− SEM) on the active (black bars) or inactive lever (white bars) or [C] mean total sucrose pellets (+/− SEM; gray bars) following pretreatment with vehicle (saline; Veh) or WAY 163909 (0.5, 1 or 2 mg/kg, i.p., 15 min) (left panel) or following pretreatment with the 5-HT2CR antagonist SB 242084 (0.5 mg/kg, i.p., 15 min) plus vehicle (saline; Veh) or WAY 163909 (2 mg/kg, i.p.) (right panel) during the sucrose self-administration maintenance phase. Active lever responses resulted in the delivery of a single sucrose pellet (45 mg) according to an FR5 schedule of reinforcement and simultaneous presentation of the sucrose-paired cues. *p < 0.05 vs. Veh; ^p < 0.05 vs. WAY 163909 (2 mg/kg).

Fig. 5. WAY 163909 does not alter sucrose cue-evoked reinstatement

[A] Mean responses (+/− SEM) on the active (black circles) or inactive lever (white circles), and the total number of sucrose pellets (+/− SEM; gray circles) are presented for the acquisition phase of sucrose self-administration under FR1 – FR5 schedules of reinforcement. Active lever responses resulted in the delivery of a single sucrose pellet (45 mg) and simultaneous presentation of the sucrose-paired cues. [B] Mean (+/− SEM) total number of responses on the active (filled bars) or inactive levers (open bars) following extinction (“Extinction Baseline”) and upon pretreatment with vehicle (saline; Veh) or WAY 163909 (0.5 or 1.5 mg/kg, i.p.) on the test day for reinstatement of extinguished sucrose-seeking behavior. Reinstatement was initiated by a single non-contingent presentation of sucrose-paired cues (pump and stimulus light). Each active lever press resulted in the presentation of the conditioned stimuli in the absence of sucrose pellet delivery. *p < 0.05 vs. Extinction.