A role for reward valuation in the serotonergic modulation of impulsivity

Rationale Impulsive behavior is a deleterious component of a number of mental health disorders but has few targeted pharmacotherapies. One contributing factor to the difficulty in understanding the neural substrates of disordered impulsivity is the diverse presentations of impulsive behavior. Defining the behavioral and cognitive processes which contribute to different subtypes of impulsivity is important for understanding the neural underpinnings of dysregulated impulsive behavior. Methods Using a mouse model for disordered impulsivity, our goal was to identify behavioral and cognitive processes that are associated with increased impulsivity. Specifically, we were interested in the facets of impulsivity modulated by serotonin signaling. We used mice lacking the serotonin 1B receptor (5-HT1BR) and measured different types of impulsivity as well as goal-directed responding, extinction, habitual-like behavior, cue reactivity, and reward reactivity. Results Mice lacking expression of 5-HT1BR had increased levels of impulsive action, goal-directed responding, and motivation, with no differences seen in rate of extinction, development of habitual behavior, delay discounting, or effort-based discounting. Interestingly, mice lacking 5-HT1BR expression also showed an overall increase in the choice of higher value rewards, increased hedonic responses to sweet rewards, and responded more for cues that predict reward. We developed a novel paradigm to demonstrate that increasing anticipated reward value could directly increase impulsive action. Furthermore, we found that 5-HT1BR KO-induced impulsivity could be ameliorated by decreasing the reward value relative to controls, suggesting that the increased 5-HT1BR-associated impulsive action may be a result of increased reward valuation. Conclusions Taken together, these data show that the effects of serotonin on impulsive action are mediated through the modulation of hedonic value, which may alter the reward representations that motivate action. Overall, this data supports a role for reward value as an important substrate in impulsive action which may drive clinically relevant increases in impulsivity.

A role for reward sensitivity in the serotonergic modulation of impulsivity

While the neural substrates of impulsive behavior are commonly studied in humans and preclinical models, the behavioral substrates which contribute to impulsivity are still understudied. Understanding the behavioral underpinnings of impulsive behavior will allow us to better model disorders of impulsive behavior in animals, and also help more clearly define the underlying neural circuits. Our goal here was to explore behavioral correlates and effectors of impulsive behavior, using a mouse model for disordered impulsivity, namely mice lacking the serotonin 1B receptor (5-HT1BR). Our past work, along with others’, implicates 5-HT1BR in the regulation of impulsivity, specifically, impulsive action. In mice, the absence of 5-HT1BR expression in adulthood results in a reduced ability to wait or withhold responses. We report here, that in addition to increased impulsive action, mice lacking expression of 5-HT1BR show increased goal-directed responding and motivation, with no differences in extinction, development of habitual behavior, or impulsive choice measured in a delay discounting paradigm. Interestingly, mice lacking 5-HT1BR also show increased hedonic responses to sweet rewards. Finally, using a newly developed paradigm, we report that increasing reward value increases impulsive action on a trial-by-trial basis, showing how changing reward value can directly influence impulsive behavior. Taken together, these data support the hypothesis that the effects of 5-HT1BR on impulsive action reflect enhanced reward sensitivity, and point to potential neural and phenotypic causes for clinically-relevant increases in impulsivity.