Advancing Neuropsychiatric Medications Development: Ketamine-Induced Rescue of Anhedonia and Attentional Deficits Induced by Chronic Ecologically Relevant Stress

Abstract ID 96574 Poster Board 505 Currently available pharmacotherapeutics for major depression leave many patients with unmet treatment needs. One obstacle to medications development is the translatability of preclinical models and their predictive relevance in clinical settings. As such, there is a need to optimize animal models designed to examine the ability of drug treatment to rescue diverse symptoms of depression under chronic stress conditions. Both anhedonia, the loss of pleasure to previously rewarding stimuli, and deficits in attentional processes are prevalent phenotypes in patients experiencing depression. In the present studies, reward responsivity and sustained vigilance were used as key behavioral metrics to evaluate the effects of two chronic ecologically relevant stressors, inescapable ice water and isolated restraint. These stressors were chosen instead of contrived alternatives (e.g., electric shock) due to their prominence in the evolutionary history of rodent species. Two touchscreen-based behavioral assays were used, the Probabilistic Reward Task (PRT) and the Psychomotor Vigilance Task (PVT). Both tasks are reverse-translated assays from clinical work and are designed to provide objective measures of reward sensitivity (anhedonia) and sustained vigilance (attentional deficits), respectively. In these studies, groups of rats were trained on one of the two tasks and, following training to baseline criteria, were chronically exposed to one of the two stressors. Both stressors negatively impacted performance in both touchscreen tasks. The most persistent deficits, however, were observed on reward responsivity following exposure to chronic inescapable ice water stress. To determine the ability of pharmacological rescue of these observed anhedonic phenotypes, administration of ketamine was studied given its known efficacy as a rapid-acting FDA-approved treatment for depression. Results show in rats exhibiting anhedonic-like phenotypes under conditions of chronic stress, ketamine was able to rescue blunted reward responsivity and do so with a prolonged time course of nearly one week. Taken together, these studies contribute to validating and optimizing a preclinical model for assessing the efficacy of novel therapeutics designed to be fast-acting antidepressants using reverse-translated performance under chronic ecologically relevant stress conditions.