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

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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.

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Data Availability

The raw data supporting the conclusion of this article will be made available by the authors, without undue reservation.

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Acknowledgements

The authors thank Dr. Xuemei Huang for her insight into these results and supportive comments during the study, and Susan Kocher and Natalia Loktionova for their invaluable technique support.

This work was supported by the Brain & Behavior Research Foundation Young Investigator Award (19469), Children’s Miracle Network Research Grant (2022–2023) and Trainee Grant (2023-2024), the National Institutes of Health (R01 NS105471, RF1 AG071675), and the Penn State Translational Brain Research Center.

Portions of this work were presented at the International Behavioral Neuroscience Society Annual Meeting in June 2023 (Niagara Falls, Ontario, Canada)

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Authors and Affiliations

  1. Neuroscience Program, Penn State University College of Medicine, Hershey, PA, 17033, USA

    Jack X. Cimino

  2. Department of Pharmacology, Penn State University College of Medicine, Hershey, PA, 17033, USA

    Mi Zhou, Richard B. Mailman & Yang Yang

  3. Department of Neurology, Penn State University College of Medicine, Hershey, PA, 17033, USA

    Mi Zhou & Richard B. Mailman

  4. Department of Psychiatry and Behavioral Health, Penn State University College of Medicine, Hershey, PA, 17033, USA

    James Waxmonsky

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Correspondence to Yang Yang.

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Conflict of interest

RBM is a consultant for Cerevel Therapeutics and also is an inventor of D1-related technology. His conflicts of interest have been disclosed and are managed by the Pennsylvania State University. JW has a research contract with Supernus Pharmaceuticals and is a consultant for Ironshore Pharmaceuticals and Adlon Pharmaceuticals.

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Cimino, J.X., Zhou, M., Waxmonsky, J. et al. Characterization of behavioral changes in T-maze alternation from dopamine D1 agonists with different receptor coupling mechanisms. Psychopharmacology 240, 2187–2199 (2023). https://doi.org/10.1007/s00213-023-06440-5

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  • DOI: https://doi.org/10.1007/s00213-023-06440-5

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