Chronic ecologically relevant stress effects on reverse-translated touchscreen assays of reward responsivity and attentional processes in male rats: Implications for depression.

Stagnation in the development of novel therapeutic strategies for treatment-resistant depression has encouraged continued interest in improving preclinical methods. One tactic prioritizes the reverse translation of behavioral tasks developed to objectively quantify depressive phenotypes in patient populations for their use in laboratory animals via touchscreen technology. After cross-species concordance in task outcomes under healthy conditions is confirmed, construct validity can be further enhanced by identifying environmental stressors that reliably produce deficits in task performance that resemble those in depressive participants. The present studies characterized in male rats the ability of two chronic ecologically relevant stressors, inescapable ice water or isolated restraint, to produce depressive-like behavioral phenotypes in the Probabilistic Reward Task (PRT) and Psychomotor Vigilance Task (PVT). These tasks previously have been reverse-translated using touchscreen technology for rodents and nonhuman primates to objectively quantify, respectively, reward responsivity (anhedonia) and attentional processes (impaired cognitive function), each of which are core features of major depressive disorder. In the PRT, both inescapable ice water and isolated restraint produced persistent anhedonic phenotypes compared to non-stressed control performance (i.e., significantly blunted response bias for the richly rewarded stimulus). In the PVT, both chronic stressors impaired attentional processing, revealed by increases in titrated reaction times; however, these deficits largely subsided by the end of the chronic condition. Taken together, these findings confirm the ability of reverse-translated touchscreen tasks to effectively generate behavioral phenotypes that exhibit expected deficits in performance outcomes following exposure to chronic ecologically relevant stress. In turn, this approach is well positioned to appraise the ability of candidate therapeutics to attenuate or reverse such behavioral deficits and, thereby, contribute to preclinical medications development for treatment-resistant depression.

A Multimodal Preclinical Assessment of MDMA in Female and Male Rats: Prohedonic, Cognition Disruptive, and Prosocial Effects.

Background: Frontline antidepressants such as selective serotonin reuptake inhibitors (SSRIs) leave many patients with unmet treatment needs. Moreover, even when SSRIs reduce depressive symptoms, anhedonia, the loss of pleasure to previously rewarding activities, often remains unabated. This state of affairs is disheartening and calls for the development of medications to more directly treat anhedonia. The atypical psychedelic 3,4-methylenedioxymethamphetamine (MDMA) might have promise as a prohedonic medication given its efficacious applications for treatment-resistant post-traumatic stress disorder and comorbid depression. However, in addition to its prosocial effects as an entactogen, MDMA is also associated with neurotoxic cognitive deficits. The present studies were designed to examine the relative potency of MDMA in female and male rats across three distinct behavioral domains to assist in defining a preclinical profile of MDMA as a candidate prohedonic therapeutic. Methods: First, signal detection metrics of reward responsivity were examined using the touchscreen probabilistic reward task (PRT), a reverse-translated assay used to objectively quantify anhedonic phenotypes in humans. Second, to probe potential cognitive deficits, touchscreen-based assays of psychomotor vigilance and delayed matching-to-position were used to examine attentional processes and short-term spatial memory, respectively. Finally, MDMA's entactogenic effects were studied via pairwise assessments of social interaction facilitated by machine-learning analyses. Results: Findings show (1) dose-dependent increases in reward responsivity as quantified by the PRT, (2) dose-dependent deficits in attention and short-term memory, and (3) dose-dependent increases in aspects of prosocial interaction in male but not female subjects. Neither the desirable (prohedonic) nor undesirable (cognition disruptive) effects of MDMA persisted beyond 24 h. Conclusions: The present results characterize MDMA as a promising prohedonic treatment, notwithstanding some liability for short-lived cognitive impairment following acute administration.