Environmental determinants of ketamine's prohedonic and antianhedonic efficacy: Persistence of enhanced reward responsiveness is modulated by chronic stress.

Ketamine, a dissociative anesthetic with well documented abuse liability, can also provide rapid-onset and persistent antidepressant effects and is currently used for the management of treatment-resistant depression. Although the precise neurobiological mechanisms underlying its antidepressant actions are not fully determined, a critical feature of ketamine's clinical efficacy may be its antianhedonic action. Anhedonia is an endophenotype of depression defined by decreased responsivity to previously rewarding stimuli and is generally not ameliorated by conventional antidepressants, emphasizing the need to examine underlying behavioral mechanisms of action. In this study, the probabilistic reward task, a reverse-translated assay originally designed to objectively quantify anhedonic phenotypes in human subjects, was used in rats to examine ketamine's effects on reward responsiveness under conditions without programmed stressors (3.2-32.0 mg/kg) or during ongoing chronic exposure to ecologically relevant stress (10.0 mg/kg). Results showed that under conditions without programmed stress, ketamine produced significant prohedonic effects in the probabilistic reward task, defined by increases in reward responsiveness that dissipated within 24 hours. In rats exposed to ongoing chronic stress, ketamine produced significant antianhedonic effects, defined by the rescue of blunted reward responsiveness, that persisted for nearly 1 week. Taken together, the prolonged antianhedonic effects of ketamine in rats experiencing chronic stress, compared with the shorter-lived prohedonic effects in subjects without exposure to programmed stressors, are striking and highlight the role of environmental determinants in the effects of ketamine on behavioral processes. Moreover, the translational nature of this experimental design may offer the opportunity to accelerate development of novel antianhedonic therapeutics. SIGNIFICANCE STATEMENT: Although ketamine is used for the management of treatment-resistant depression, its precise behavioral mechanisms of action are not fully delineated. Emerging evidence suggests the attenuation of anhedonia plays a key role in its rapid-acting therapeutic efficacy. To evaluate this possibility, the effects of ketamine were studied using a reverse-translated assay of reward responsiveness in rats and documented to be short-lived (prohedonic) under nonstressful conditions and persistent (antianhedonic) under stressful conditions, informing ketamine effects in healthy versus depressed individuals.