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

Abstract

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.

Keywords: age-related cognitive decline; dopamine D1 agonist; functional selectivity/signaling bias; temporal order recognition; working memory.

Figure 1:. Performance of TOR task by rats of three different age groups (youngest, middle, and oldest).

A: Task diagram. B: Individual performance distribution among each age group (violin bars). Horizontal lines show median; dots represent each individual rat; dash line indicates I_TOR=0.7, which serves as the criteria to categorize “good (white) / bad (grey) performer”. C: Percentage of good/bad performers in each age group. Note the age-related decline in novelty seeking (good performer). * = p<0.05.

Figure 2:. Change in the TOR performance (I_TOR) after D₁ agonists 2MDHX or PF.

Each D₁ agonist was administered at its respective individual optimal dose on three different age groups of rats. A: Comparison of the I_TOR among vehicle and drugs. B: Comparison of the optimal dose among three age groups. Doses are log-transformed. Bars represent mean ± SD; dots and lines represent individual rats. * = p<0.05; *** = p<0.001. Note the significant changes in older rats and the lower optimal dose of PF needed for older rats.

Figure 3:. Baseline TOR and effects of D₁ agonists.

A: Change of I_TOR for rats who performed better during baseline vehicle session vs rats who performed worse during baseline vehicle session. Dots and lines represent individual rats. White = good performers; gray = bad performers. B: Percentage of good performers whose I_TOR was slightly increased (leftward line shadow) / decreased (vertical line shadow) after D₁ agonist administration. C: Comparison of optimal dose for good vs bad performers. Doses are log-transformed. Bars represent mean ± SD; circles represent individual rats. * = p<0.05; **** = p<0.0001.