Dopamine D1 Agonists, Working Memory, and the Prefrontal Cortex: Effect of Receptor Functional Selectivity/Signaling Bias

Abstract

Dopamine D1 agonists produce an ‘inverted‐U’ dose‐response on working memory‐related behavioral tasks (i.e., low doses improve but high doses have no effect or tend to impair performance). This dose‐dependency has been observed at the single neuron level in the prefrontal cortex, where the cellular basis of working memory is represented. Few studies, however, have examined this process at the neuron population level and its signaling mechanism(s) is still unclear. In the current study, two D1 agonists, 2‐methyldihydrexidine (2MDHX) and CY208,243 (CY208), were examined and compared in rats performing a spatial working memory‐related T‐maze task. 2MDHX is a full agonist at adenylate cyclase and a super‐agonist at β‐arrestin recruitment, whereas CY208 has relatively high intrinsic activity at adenylate cyclase, but much lower at β‐arrestin recruitment. Both compounds had inverted U‐dose response curves at both the behavioral and prefrontal neuron population level, albeit with distinct differences. At behavioral level, they both caused similar improvement with high potency (10 nmol/kg). Conversely, the right‐hand (descending) part of the inverted U dose‐response curve had a great slope for 2MDHX than for CY208, suggesting an extended effective range for a compound with lower β‐arrestin activity. At the neuron population level, both drugs affected the percentage, uniformity, and ensemble strength of sensitivity in a dose‐dependent manner, but 2MDHX influenced neuron activity more before the choice in the T‐maze task whereas CY208 influenced it more after the choice. As the off‐target effects were not likely engaged at the very low doses (i.e., nmol/kg range) utilized in the current study, the differences between 2MDHX and CY208 most likely are related to their specific D1 functional selectivity profiles. The ‘inverted‐U’ dose‐response of D1 agonists on cognitive performance has been observed in many of animal models and confirmed in humans. Although the cognitive improvement at the optimal dose is impressive, the biphasic effect complicates potential clinical use of D1 drugs. Our data indicate that differential signaling may play a role in D1‐related dose‐dependent regulation of cognition, and suggest that D1‐related dose‐dependent regulation of working memory could be modified by functionally selective/biased ligands. This may help guide the discovery of novel D1 compounds that may yield a more monotonic response and therefore translate to the clinic more readily.Support or Funding InformationBrain & Behavior Research Foundation Young Investigator Grant # 19469 to YY, the 2017 Children’s Miracle Network Research Grant #10 to YY and RBM, the Penn State Translational Brain Research Center, and R01 NS105471 to RBM. Conflict of interest: Dr. Mailman is an inventor on patents related to D1 ligand discovery, and this conflict is disclosed and managed by the Penn State College of Medicine.