RT Journal Article
SR Electronic
T1 An Interaction between Serotonin Receptor Signaling and Dopamine Enhances Goal-Directed Vigor and Persistence in Mice
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 2149
OP 2162
DO 10.1523/JNEUROSCI.2088-17.2018
VO 38
IS 9
A1 Matthew R. Bailey
A1 Olivia Goldman
A1 Estefanía P. Bello
A1 Muhammad O. Chohan
A1 Nuri Jeong
A1 Vanessa Winiger
A1 Eileen Chun
A1 Elke Schipani
A1 Abigail Kalmbach
A1 Joseph F. Cheer
A1 Peter D. Balsam
A1 Eleanor H. Simpson
YR 2018
UL http://www.jneurosci.org/content/38/9/2149.abstract
AB 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.