Effect of Functionally Selective Dopamine D₁ Receptor Agonists on Complex Cognitive Processes in a Rodent Touchscreen...

Dopamine D₁ receptor (D₁R) signaling in the brain has been strongly implicated in multiple cognitive processes, with D₁ agonists known to enhance performance. The development of functionally selective D₁ agonists that differentially activate D₁R-mediated cAMP versus β-arrestin signaling may offer precision therapy if we understand how signaling bias impacts integrated cognitive processes in complex tasks. We therefore examined the effects of two selective D₁ agonists, 2-methyldihydrexidine (2MDHX) and PF-06256142 (PF), on a rodent touchscreen-based Trial-Unique Nonmatching-To-Location task. Primarily assessing both spatial working memory and pattern separation in adult male rats, this behavioral paradigm requires greater cognitive demands to maintain performance throughout the testing session, significantly increasing task complexity. Our results revealed an inverted U-shaped dose response curve for both compounds, aligning with our previously published work, but did not demonstrate marked improvement in task performance. Subjects treated with the mid-dose range (10, 100, and 1,000 nmol/kg) generally performed similarly to, or slightly below, vehicle treated subjects whereas the highest dose administered (10,000 nmol/kg) significantly reduced task performance and engagement. The behavioral effects were similar for PF and 2MDHX, suggesting that functional selectivity/bias (at least for the cAMP versus β-arrestin signaling pathways) was not a major factor in this cognitive task. In addition to providing new information about how D₁ agonists might affect different aspects of cognition, our data underscores the importance of dose optimization and task structure and showcases the translational value of touchscreen-based paradigms when assessing potential cognitive enhancers.