Dopamine D1 agonists enhance cognition, but the role of different signaling pathways (e.g., cAMP or β-arrestin) is unclear. The current study compared 2-methyldihydrexidine and CY208,243, drugs with different degrees of both D1 intrinsic activity and functional selectivity. 2-Methyldihydrexidine is a full agonist at adenylate cyclase and a super-agonist at β-arrestin recruitment, whereas CY208,243 has relatively high intrinsic activity at adenylate cyclase, but much lower at β-arrestin recruitment. Both drugs decreased, albeit in dissimilar ways, the firing rate of neurons in prefrontal cortex sensitive to outcome-related aspects of a working memory task. 2-Methyldihydrexidine was superior to CY208,243 in prospectively enhancing similarity and retrospectively distinguishing differences between correct and error outcomes based on firing rates, enhancing the micro-network measured by oscillations of spikes and local field potentials, and improving behavioral performance. This study is the first to examine how ligand signaling bias affects both behavioral and neurophysiological endpoints in the intact animal. The data show that maximal enhancement of cognition via D1 activation occurred with a pattern of signaling that involved full unbiased intrinsic activity, or agonists with high β-arrestin activity.
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The authors thank Dr. David L. Gray and Rebecca O’Connor of Pfizer Central Research for their insight and technical assistance, and Susan Kocher for her invaluable technique support. This work was supported by: Brain & Behavior Research Foundation Young Investigator Grant; Children’s Miracle Network Research Grant; the Penn State Hershey Neuroscience Institute; the Parkinson’s Disease Gift Fund of the Penn State Milton S. Hershey Medical Center; and R01 MH040537, U19 MH082441, and R01 NS105471. Portions of this work were presented at the Society for Neuroscience meetings in November 2014 (Washington, DC) and November 2016 (San Diego, California).
Conflict of interest
RBM has a potential conflict-of-interest related to his role as an inventor on patents related to dopamine D1 agonists, the ownership of which has been assigned to university foundations. These issues are managed by the Conflict-of-Interest system at the Penn State University and its College of Medicine. The remaining authors declare that they have no conflict of interest.
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Yang, Y., Lee, SM., Imamura, F. et al. D1 dopamine receptors intrinsic activity and functional selectivity affect working memory in prefrontal cortex. Mol Psychiatry 26, 645–655 (2021). https://doi.org/10.1038/s41380-018-0312-1