Dopamine D₁ Receptor Agonists Rescue Age-related Decline in Temporal Order Memory

Dopamine D₁ receptor agonists improve spatial working memory, but their effects on temporal order memory, particularly prone to the effects of aging, have not been studied. Two D₁ agonists, PF6256142 (PF) and 2-methyldihydrexidine (2MDHX), were examined for their effects in a rodent temporal order recognition task. Our results are consistent with the hypothesis that there is an age-related decline in rodent temporal order memory. The data also show that either agonist rescues the poor memory performance with a large effective size. Interestingly, the optimal effective dose varied among individual rats of different age groups. PF showed greater potency for older rats, whereas 2MDHX showed better overall population effectiveness. Both PF and 2MDHX have high intrinsic activity at rodent D₁-mediated cAMP synthesis. Conversely, at D₁-mediated β-arrestin recruitment, PF has essentially no intrinsic activity, whereas 2MDHX is a super-agonist. These findings suggest that D₁ agonists have potential to treat age-related cognitive decline, and the pattern of functional selectivity may be useful for developing drugs with an improved therapeutic index.