An Interaction between Serotonin Receptor Signaling and Dopamine Enhances Goal-Directed Vigor and Persistence in Mice

Abstract

The functionally selective 5-HT2C receptor ligand SB242084 can increase motivation and have rapid onset anti-depressant-like effects. We sought to identify the specific behavioral effects of SB242084 treatment and elucidate the mechanism in female and male mice. Using a quantitative behavioral approach, we determined that SB242084 increases the vigor and persistence of goal-directed activity across different types of physical work, particularly when work requirements are demanding. We found this influence of SB242084 on effort, rather than reward to be reflected in striatal DA measured during behavior. Using in vivo fast scan cyclic voltammetry, we found that SB242084 has no effect on reward-related phasic DA release in the NAc. Using in vivo microdialysis to measure tonic changes in extracellular DA, we also found no changes in the NAc. In contrast, SB242084 treatment increases extracellular DA in the dorsomedial striatum, an area that plays a key role in response vigor. These findings have several implications. At the behavioral level, this work shows that the capacity to work in demanding situations can be increased, without a generalized increase in motor activity or reward value. At the circuit level, we identified a pathway restricted potentiation of DA release and showed that this was the reason for the increased response vigor. At the cellular level, we show that a specific serotonin receptor cross talks to the DA system. Together, this information provides promise for the development of treatments for apathy, a serious clinical condition that can afflict patients with psychiatric and neurological disorders.SIGNIFICANCE STATEMENT Motivated behaviors are modulated by reward value, effort demands, and cost-benefit computations. This information drives the decision to act, which action to select, and the intensity with which the selected action is performed. Because these behavioral processes are all regulated by DA signaling, it is very difficult to influence selected aspects of motivated behavior without affecting others. Here we identify a pharmacological treatment that increases the vigor and persistence of responding in mice, without increasing generalized activity or changing reactions to rewards. We show that the 5-HT2C-selective ligand boosts motivation by potentiating activity-dependent DA release in the dorsomedial striatum. These results reveal a novel strategy for treating patients with motivational deficits, avolition, or apathy.

Keywords: 5-HT2C; DA; fast scan cyclic voltammetry; goal-directed behavior; in vivo microdialysis; striatum.

Figure 1.

Systemic SB242084 treatment does not alter animal's choice for different types of reward. a, Schematic diagram of the CVC task. b, Choice functions of proportion of sucrose choices made in the CVC task for 5% sucrose (dashed connecting lines) and 20% sucrose (solid connecting lines) following either vehicle (blue) or SB (red) treatment. c, Individual PSEs following either vehicle (blue) or SB treatment (red) plot for 5% or 20% sucrose versus pellet. N = 16 mice. Pell = Pellet, Suc = Sucrose.

Figure 2.

Systemic SB242084 does not alter DA encoding of rewards or reward cues. a, Schematic diagram of the Pavlovian task. b, Demonstration of Pavlovian learning. S, Saline injection; Tx, treatment days. c, Normalized CS⁺ and CS⁻ DA response traces. Solid vertical line indicates CS onset. Dashed vertical line indicates 0.5 s before CS onset, used as background value. d, Maximal CS⁺ and CS⁻ evoked DA release. e, CS⁺ and CS⁻ accumulated DA release (area under the curve). f, US⁺ and US⁻ DA response traces. Solid vertical line indicates CS offset (and reward delivery in CS⁺ trials). g, Maximal US⁺ and US⁻ evoked DA release. h, US⁺ and US⁻ accumulated DA release (area under the curve). d, e, g, h, Data points indicate individual trials, line indicates mean, and error bars indicate SEM. N = 5 mice. *p ≤ 0.05.

Figure 3.

Systemic SB242084 treatment does not alter animal's choice for different forms of work. a, Schematic diagram of the CEC task. b, Average function of proportion of hold choices made in the CEC task following vehicle (blue) or SB (red) treatment. c, The PSE of individual subjects between lever pressing and holding for 10 s following vehicle (blue) or SB (red) treatment. d, Vehicle PSE × SB PSE scatter plot. N = 15 mice. PL = Press Lever, HL = Hold Lever.

Figure 4.

Systemic SB242084 enhances motivation in goal-directed activity by increasing response vigor. a, Average press rate during a PR × 2 lever pressing task. b, Press rate as a function of press requirement. c, Schema of the parameters analyzed include the number of presses within a bout of pressing (bout length). The duration of pause between active pressing bouts (pause duration). The interval between lever presses within a bout of pressing (IRT), the pause between reward delivery and the first press toward the next ratio requirement (PRP). d, Average bout length. e, Bout length for each press requirement. f, Average pause duration. g, Pause duration for each press requirement. h, Average IRT. i, IRTs for each press requirement. j, Average PRP. k, PRP for each press requirement. All results are presented under vehicle and SB242084 treatment. N = 21 mice. ***p ≤ 0.001, ****p ≤ 0.0001.

Figure 5.

SB242084-enhanced goal-directed activity is not due to an increased resistance to extinction. a, Lever press rates during the RR20 session before the extinction test in groups assigned to either vehicle (Veh) or SB treatment. b, Total lever presses in 5 min bins during the extinction session. Lines indicate nonlinear fit of the group mean data to the exponential decay function: Y = (a × exp (−b × x). c, Peak press rate (a) during the extinction session. d, Rate of decay (b) during extinction. e, Goodness of fit (R²) during the extinction session. a, c–e, Symbols indicate individual subject's data, lines indicate group mean, and error bars indicate SEM. N = 14 mice per group.

Figure 6.

Systemic SB242084 is most beneficial when work requirements are high. a, Lever press rates per second as a function of time within the trial are plotted for each FR schedule: FR10, FR20, FR40, and FR80. Data are mean ± SEM for press rates from 15 subjects and 20 trials per ratio. b, Time to complete FR trials is presented for each trial type. c, IRTs are presented for each trial type. Data points represent mean values for each treatment. Error bars indicate SEM. N = 15 mice. **p ≤ 0.01, ****p ≤ 0.0001.

Figure 7.

In an effort-based choice task (RR15 for milk vs free chow), systemic SB242084 potentiates task-dependent DA release in the dorsomedial striatum and not the NAc. a, DMS DA level across time in each condition tested: Work + Vehicle, Work + SB, No Work + SB. b, Maximum increase in DMS DA release during behavior. **Overall effect of condition. c, NAc DA level across time in each condition tested: Work + Vehicle, Work + SB, No Work + SB. d, Maximum increase in NAc DA release during behavior. e, Placement of the microdialysis probes. Light gray represents NAc probes. Dark gray represents DMS probes. Positions of the sections relative to bregma are provided. f, Total lever presses during the 60 min behavioral session increased with SB242084. g, Average press initiation interval decreased with SB242084. N = 8 mice. *p ≤ 0.05, **p ≤ 0.01.

Figure 8.

In the effort-based choice task (RR15), DA receptor blockade in the DMS reduces responding and blocks the invigorating effect of systemic SB242084. Top row indicates the effect of DMS infusion of aCSF or 1.5 μg of flupenthixol (FPX). a, Average press initiation interval. b, Total lever presses. c, Rewards earned. d, Percentage of uncollected earned rewards. Bottom row indicates the effect of 0.5 μg FPX infusion in the DMS with and without intraperitoneal SB injections, compared with baseline (Vehicle injection + Sham infusion). e, Average press initiation interval. f, Total lever presses. g, Rewards earned. h, Percentage of uncollected earned rewards. i, Infusion sites within the DMS. Positions of the sections relative to bregma are provided. N = 7 mice. *p ≤ 0.05.