D1 dopamine receptors intrinsic activity and functional selectivity affect working memory in prefrontal cortex

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.