Investigating the Dopaminergic and Glucocorticoid Systems as Underlying Mechanisms of Anhedonia

Abstract

Anhedonia, a severe deficit in reward processing, is an endophenotype of several neuropsychiatric disorders (APA, 2000) and increases susceptibility to depression (Atherton et al., 2015), substance abuse (Hatzigiakoumis et al., 2011), and suicidality (Winer et al., 2016). Recent literature suggests that anhedonia reflects a maladaptive interaction between reward circuitry and stress, the former being mediated by the mesolimbic dopamine (DA) system and the latter by the glucocorticoid system (Vrieze et al., 2013). The role of the DA system in the development and maintenance of anhedonia has been studied extensively, but little is known about the contribution of the glucocorticoid system to this process. The goal of the current study was to investigate the dopaminergic and glucocorticoid systems as underlying mechanisms of anhedonia using a validated rat test of anhedonia, the probabilistic reward task (PRT). In this task, rats learned to discriminate between two ambiguous tones for a sucrose reward. During testing, one lever was programmed to produce three times more reward than the other lever. Similar to healthy humans, rats develop a response bias toward the more frequently reinforced stimulus, regardless of which tone is presented. Consistent with prior literature, the response bias was enhanced following amphetamine- (AMPH) induced DA activation, and reduced following pramipexole- (PRAMI) induced DA inhibition. Additionally, a 21-day chronic mild stress (CMS) regimen attenuated the response bias in a subpopulation of animals relative to no stress controls. Finally, the glucocorticoid antagonist, mifepristone (MIFE), had no effect on the response bias relative to saline (SAL); however, the glucocorticoid agonist, dexamethasone (DEX), attenuated the response bias relative to both SAL and MIFE. These results confirm a role of DA in reward processing, and highlight an additional contribution of the glucocorticoid system in the mediation of this effect. Thus, it is plausible that chronic stress directly interferes with normal mesolimbic DA functioning, which leads to an overall impairment in reward responsiveness. These findings underscore the importance of treatment directed toward the DA and glucocorticoid systems, rather than the current SSRI treatment. Future studies on the etiology of anhedonia should carefully investigate the interaction of these systems in reward processing.