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

Abstract

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.

Keywords: Dopamine D1 agonist; Functional selectivity/signaling bias; Rodent T-maze alternation; Spatial working memory.

Fig. 1

Change in the correct rate after 2MDHX and CY208 were administered a: T-maze alternation task diagram. b: Change in the correct rate after 2MDHX or CY208 was administered at different nmol/kg doses. c: Change in the correct rate after 2MDHX or CY208 was administered at their respective optimal (grey shade) or detrimental (black shade) doses. d: Summary of the optimal and detrimental doses for each rat. Violin bars show mean and distribution; dots in b and c and lines in d represent an individual rat. Note the significant changes in the correct rate and the animal-to-animal variation induced by 2MDHX and CY208 respectively. *, **, and *** indicate p < 0.05, 0.01, or 0.001 respectively

Fig. 2

The choice latency and its relation to the correct rate from the vehicle sessions. a: Summary of the average correct and the incorrect choice latency. b: Summary of the latency trial-to-trial variation. c: Correlation between the correct and the incorrect choice latency. d: Correlation between the latency trial-to-trial variation and the correct rate. Bars show mean and SD; lines in a and b and dots in c and d represent each individual test session. Note the difference between correct and incorrect choices

Fig. 3

Change in the choice latency after 2MDHX or CY208 was administered at different doses. Top panel shows the average latency; bottom shows the latency trial-to-trial variation. a: Summary of the correct choices. b: Summary of the incorrect choices. Bars show mean and SD; dots represent each individual rat. Note 10 nmol/kg 2MDHX significantly decreased the incorrect choice latency. ** indicate p < 0.01

Fig. 4

Change in the choice latency after 2MDHX or CY208 was administered at their respective optimal (gray) or detrimental (black) doses. a, b: Summary of the correct choices. c-d: Summary of the incorrect choices. a, c: the average latency; b & d: the latency trial-to-trial variation. Bars show mean and SD; dots represent each individual rat. In panel d, for each rat, there was only one or no incorrect choice after 2MDHX was administered at its optimal dose, therefore not applicable to calculate CV for latency trial-to-trial variation. Note the incorrect choice latency had significantly increased trial-to-trial variation after CY208 was administered at its detrimental dose. * indicate p < 0.05

Fig. 5

Correlations between the doses that caused changes in the choice latency and the doses that caused changes in the correct rate. a: The positive correlation between the detrimental dose of 2MDHX (i.e., min correct rate) and the dose to cause the longest incorrect choice latency (i.e., max incorrect latency). b: The negative correlation between the detrimental dose of CY208 (i.e., min correct rate) and the dose to cause the shortest incorrect choice latency (i.e., min incorrect latency). c: The positive correlation between the detrimental dose of CY208 (i.e., min correct rate) and the dose to cause the least trial-to-trial variation of the correct choice latency (i.e., min variation of correct latency). Dots represent each individual rat