Abstract

The functionally selective 5HT-2C receptor ligand SB242084 can increase motivation and have rapid onset anti-depressant like effects. We sought to identify the specific behavioural effects of SB242084 treatment and elucidate the mechanism in female and male mice. Using a quantitative behavioural 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 dopamine measured during behavior. Using in vivo fast scan cyclic voltammetry, we found that SB242084 has no effect on reward-related phasic dopamine release in the nucleus accumbens (NAc). Using in vivo microdialysis to measure tonic changes in extracellular dopamine, we also found no changes in the NAc. In contrast, SB242084 treatment increases extracellular dopamine 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 dopamine 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 dopamine system. Taken 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 carried out. Because these behavioural processes are all regulated by dopamine 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 dopamine release in the dorsomedial striatum. These results reveal a novel strategy for treating patients with motivational deficits, avolition or apathy.