Sex differences in lever pressing and running wheel tasks of effort-based choice behavior in rats: Suppression of high effort activity by the serotonin transport inhibitor fluoxetine.

Selective serotonin transport (SERT) inhibitors such as fluoxetine are the most commonly prescribed treatments for depression. Although efficacious for many symptoms of depression, motivational impairments such as psychomotor retardation, anergia, fatigue and amotivation are relatively resistant to treatment with SERT inhibitors, and these drugs have been reported to exacerbate motivational deficits in some people. In order to study motivational dysfunctions in animal models, procedures have been developed to measure effort-related decision making, which offer animals a choice between high effort actions leading to highly valued reinforcers, or low effort/low reward options. In the present studies, male and female rats were tested on two different tests of effort-based choice: a fixed ratio 5 (FR5)/chow feeding choice procedure and a running wheel (RW)/chow feeding choice task. The baseline pattern of choice differed across tasks for males and females, with males pressing the lever more than females on the operant task, and females running more than males on the RW task. Administration of the SERT inhibitor and antidepressant fluoxetine suppressed the higher effort activity on each task (lever pressing and wheel running) in both males and females. The serotonin receptor mediating the suppressive effects of fluoxetine is uncertain, because serotonin antagonists with different patterns of receptor selectivity failed to reverse the effects of fluoxetine. Nevertheless, these studies uncovered important sex differences, and demonstrated that the suppressive effects of fluoxetine on high effort activities are not limited to tasks involving food reinforced behavior or appetite suppressive effects. It is possible that this line of research will contribute to an understanding of the neurochemical factors regulating selection of voluntary physical activity vs. sedentary behaviors, which could be relevant for understanding the role of physical activity in psychiatric disorders.

The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation.

Effort-based decision making is studied using tasks that offer choices between high-effort options leading to more highly valued reinforcers versus low-effort/low-reward options. These tasks have been used to study the involvement of neural systems, including mesolimbic dopamine and related circuits, in effort-related aspects of motivation. Moreover, such tasks are useful as animal models of some of the motivational symptoms that are seen in people with depression, schizophrenia, Parkinson's disease, and other disorders. The present review will discuss the pharmacology of effort-related decision making and will focus on the use of these tasks for the development of drug treatments for motivational dysfunction. Research has identified pharmacological conditions that can alter effort-based choice and serve as models for depression-related symptoms (e.g., the vesicular monoamine transport-2 inhibitor tetrabenazine and proinflammatory cytokines). Furthermore, tests of effort-based choice have identified compounds that are particularly useful for stimulating high-effort work output and reversing the deficits induced by tetrabenazine and cytokines. These studies indicate that drugs that act by facilitating dopamine transmission, as well as adenosine A2A antagonists, are relatively effective at reversing effort-related impairments. Studies of effort-based choice may lead to the identification of drug targets that could be useful for treating motivational treatments that are resistant to commonly used antidepressants such as serotonin transport inhibitors.