Abstract
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.
Significance statement This study explored how functionally selective D1 receptor agonists may serve as potential cognitive enhancers. It highlighted the critical role of dose optimization in balancing efficacy and tolerability. By using a highly translational touchscreen-based task, these findings advance our understanding of how D1R signaling bias influences working memory and helps provide a footing for future research into clinical translation.
Footnotes
RBM has intellectual property related to dopamine D1 agonists and their use that are not actively under development but could be constructed as a conflict-of-interest that has been managed by the Penn State College of Medicine and the University of Virginia. The remaining authors declare no competing financial interests.
This work was supported by the National Institutes of Health (R01 AG071675, TL1 TR002016, UL1 TR002014), Children’s Miracle Network Research Grant (2022–2025) and Trainee Grant (2023-2025), and the Penn State Center for Biodevices Grace Woodward Seed Grant (2025). The authors wish to thank Susan Kocher and Natalia Loktionova for their invaluable technical support, Rachel Kang and Scott Eckert for their coding assistance, and Drs. Sue Grigson and Mi Zhou (周密) for their insight and supportive comments during this study. In addition, this research would not have been possible without the dedication and sacrifice of the rodents involved, and the authors would like to acknowledge their irreplaceable contribution to the advancement of science.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
