Translational Assessments of Reward Responsiveness in the Marmoset

Abstract

Background: Anhedonia, the loss of pleasure in previously rewarding activities, is a prominent feature of major depressive disorder and often resistant to first-line antidepressant treatment. A paucity of translatable cross-species tasks to assess subdomains of anhedonia, including reward learning, presents a major obstacle to the development of effective therapeutics. One assay of reward learning characterized by orderly behavioral and pharmacological findings in both humans and rats is the probabilistic reward task. In this computerized task, subjects make discriminations across numerous trials in which correct responses to one alternative are rewarded more often (rich) than correct responses to the other (lean). Healthy control subjects reliably develop a response bias to the rich alternative. However, participants with major depressive disorder as well as rats exposed to chronic stress typically exhibit a blunted response bias. Methods: The present studies validated a touchscreen-based probabilistic reward task for the marmoset, a small nonhuman primate with considerable translational value. First, probabilistic reinforcement contingencies were parametrically examined. Next, the effects of ketamine (1.0-10.0 mg/kg), a US Food and Drug Administration-Approved rapid-Acting antidepressant, and phencyclidine (0.01-0.1 mg/kg), a pharmacologically similar N-methyl-D-Aspartate receptor antagonist with no known antidepressant efficacy, were evaluated. Results: Increases in the asymmetry of rich:lean probabilistic contingencies produced orderly increases in response bias. Consistent with their respective clinical profiles, ketamine but not phencyclidine produced dose-related increases in response bias at doses that did not reduce task discriminability. Conclusions: Collectively, these findings confirm task and pharmacological sensitivity in the marmoset, which may be useful in developing medications to counter anhedonia across neuropsychiatric disorders.