Characterization of behavioral changes in T-maze alternation from dopamine D₁ agonists with different receptor coupling mechanisms

Rationale: Dopamine D₁ receptor agonists have been shown to improve working memory, but often have a non-monotonic (inverted-U) dose–response curve. One hypothesis is that this may reflect dose-dependent differential engagement of D₁ signaling pathways, a mechanism termed functional selectivity or signaling bias. Objectives and methods: To test this hypothesis, we compared two D₁ ligands with different signaling biases in a rodent T-maze alternation task. Both tested ligands (2-methyldihydrexidine and CY208243) have high intrinsic activity at cAMP signaling, but the former also has markedly higher intrinsic activity at D₁-mediated recruitment of β-arrestin. The spatial working memory was assessed via the alternation behavior in the T-maze where the alternate choice rate quantified the quality of the memory and the duration prior to making a choice represented the decision latency. Results: Both D₁ drugs changed the alternate rate and the choice latency in a dose-dependent manner, albeit with important differences. 2-Methyldihydrexidine was somewhat less potent but caused a more homogeneous improvement than CY208243 in spatial working memory. The maximum changes in the alternate rate and the choice latency tended to occur at different doses for both drugs. Conclusions: These data suggest that D₁ signaling bias in these two pathways (cAMP vs β-arrestin) has complex effects on cognitive processes as assessed by T-maze alternation. Understanding these mechanisms should allow the identification or discovery of D₁ agonists that can provide superior cognitive enhancement.