The effects of pharmacological modulation of the serotonin 2C receptor on goal-directed behavior in mice

Abstract

Rationale: Impaired goal-directed motivation represents a debilitating class of symptoms common to psychological disorders including schizophrenia and some affective disorders. Despite the known negative impact of impaired motivation, there are currently no effective pharmacological interventions to treat these symptoms.

Objectives: Here, we evaluate the effectiveness of the serotonin 2C (5-HT2C) receptor selective ligand, SB242084, as a potential pharmacological intervention for enhancing goal-directed motivation in mice. The studies were designed to identify not only efficacy but also the specific motivational processes that were affected by the drug treatment.

Methods: We tested subjects following treatment with SB242084 (0.75 mg/kg) in several operant lever pressing assays including the following: a progressive ratio (PR) schedule of reinforcement, an effort-based choice task, a progressive hold down task (PHD), and various food intake tests.

Results: Acute SB242084 treatment leads to an increase in instrumental behavior. Using a battery of behavioral tasks, we demonstrate that the major effect of SB242084 is an increase in the amount of responses and duration of effort that subjects will make for food rewards. This enhancement of behavior is not the result of non-specific hyperactivity or arousal nor is it due to changes in food consumption.

Conclusions: Because of this specificity of action, we suggest that the 5-HT2C receptor warrants further attention as a novel therapeutic target for treating pathological impairments in goal-directed motivation.

Keywords: Feeding; Locomotor activity; Motivation; Operant; SB242084; Serotonin receptor.

Fig. 1

SB242084 at 0.75 mg/kg increases responding in a progressive ratio. a Mean (SEM) number of lever presses made during the PR session. b Cumulative survival curves in the PR. c Mean (SEM) number of rewards earned in PR session. d Mean (SEM) response rate (presses/minute) as a function of trial number/reward number in the PR session. e Group average response rate from the peak of responding through the end of session fit with the negative exponential function y=a^(−b×n). f Mean (SEM) peak response rate (a) in PR session. g Mean (SEM) decay rate (b) in the PR session. Average of five consecutive days of testing in PR (3) × 2 for vehicle (n=12) and SB (n=12)-treated mice. **p<0.01

Fig. 2

SB242084 at 0.75 mg/kg increases responding for a preferred reward in an effort-based choice task. a Mean (SEM) number of lever presses made during 1 h of an effort-based choice task under different ratio schedules. b Mean (SEM) total intake (g) of freely available chow during the 1 h effort-based choice task for the different ratio schedules. Average of 5 days of testing in RR 10 (Veh/Veh), 5 days of testing in RR 10 (Veh/SB), and 5 days of testing in RR 20 (Veh/SB) for vehicle (n=12) and SB (n=12)-treated mice. *p<0.05, with Bonferoni correction for multiple comparisons

Fig. 3

SB242084 increases goal-directed action in a progressive hold down task. a Mean (SEM) number of rewards earned in the PHD session. b Mean (SEM) session duration (min) in the PHD task. c Mean (SEM) time spent successfully working in the PHD task. Average of 3 days of testing in each condition. *p<0.05, with Bonferoni correction for multiple comparisons

Fig. 4

SB242084 does not enhance non-goal-directed hyperactivity. a Mean (SEM) number of lever presses in the PHD session. b Mean (SEM) number of failed (unsuccessful) press attempts in the PHD session as a function of trial number from each subject’s last attempted trial (i.e., for each subject, 0 corresponds to their last trial and −1 corresponds to their penultimate trial, and so forth). c Mean (SEM) number of unsuccessful presses in each subject’s first five trials. d Mean (SEM) number of unsuccessful presses in each subject’s last five trials. Average of 3 days of testing in each condition. **p<0.01, with Bonferoni correction for multiple comparisons

Fig. 5

The acute effects of SB242084 (0.75 mg/kg) can be reinstated repeatedly. a Schematic of the experimental design used for the repeated administration of SB242084 experiment. b Mean (SEM) number of rewards earned in PR session for each treatment condition. c Mean (SEM) number of lever presses made in PR session for each treatment condition. d Mean (SEM) session duration (min) for each treatment condition. Average of 5 days of testing *p<0.05; **p<0.01, with Bonferoni correction for multiple comparisons