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

RationaleDopamine D-1 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 D-1 signaling pathways, a mechanism termed functional selectivity or signaling bias.Objectives and methodsTo test this hypothesis, we compared two D-1 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 D-1-mediated recruitment of & beta;-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.ResultsBoth D-1 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.ConclusionsThese data suggest that D-1 signaling bias in these two pathways (cAMP vs & beta;-arrestin) has complex effects on cognitive processes as assessed by T-maze alternation. Understanding these mechanisms should allow the identification or discovery of D-1 agonists that can provide superior cognitive enhancement.