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Behaviorally penetrant, anomalous dopamine efflux exposes sex and circuit dependent regulation of dopamine transporters

Molecular Psychiatry volume 27, pages 4869–4880 (2022)Cite this article

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Abstract

Virtually all neuropsychiatric disorders display sex differences in prevalence, age of onset, and/or clinical symptomology. Although altered dopamine (DA) signaling is a feature of many of these disorders, sex-dependent mechanisms uniquely responsive to DA that drive sex-dependent behaviors remain unelucidated. Previously, we established that anomalous DA efflux (ADE) is a prominent feature of the DA transporter (DAT) variant Val559, a coding substitution identified in two male-biased disorders: attention-deficit/hyperactivity disorder and autism spectrum disorder. In vivo, Val559 ADE induces activation of nigrostriatal D2-type DA autoreceptors (D2ARs) that magnifies inappropriate, nonvesicular DA release by elevating phosphorylation and surface trafficking of ADE-prone DAT proteins. Here we demonstrate that DAT Val559 mice exhibit sex-dependent alterations in psychostimulant responses, social behavior, and cognitive performance. In a search for underlying mechanisms, we discovered that the ability of ADE to elicit D2AR regulation of DAT is both sex and circuit-dependent, with dorsal striatum D2AR/DAT coupling evident only in males, whereas D2AR/DAT coupling in the ventral striatum is exclusive to females. Moreover, systemic administration of the D2R antagonist sulpiride, which precludes ADE-driven DAT trafficking, can normalize DAT Val559 behavioral changes unique to each sex and without effects on the opposite sex or wildtype mice. Our studies support the sex- and circuit dependent capacity of D2ARs to regulate DAT as a critical determinant of the sex-biased effects of perturbed DA signaling in neurobehavioral disorders. Moreover, our work provides a cogent example of how a shared biological insult drives alternative physiological and behavioral trajectories as opposed to resilience.

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Fig. 1: Male, but not female, DAT Val559 mice display blunted AMPH-dependent locomotor hyperactivity, accelerated CPP extinction, and blunted AMPH hypophagia.
Fig. 2: Threat aversion and social behavior in male and female DAT Val559 mice.
Fig. 3: Male and female DAT Val559 mice display distinct phenotypes in memory tasks.
Fig. 4: DAT Val559 induces elevated transporter surface trafficking and phosphorylation, but compromises uptake in the VS of females.
Fig. 5: D2R antagonism rescues select behavioral phenotypes of DAT Val559 male and female mice.
Fig. 6: Schematic diagram depicting the region-specific impacts of the DAT Val559 mutation in each sex.

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Acknowledgements

We wish to acknowledge the infrastructure support from Blakely laboratory staff members Matthew Gross, Alaina Tillman, and Zayna Gichi. The authors thank the Vanderbilt and Florida Atlantic University (FAU) Mouse Neurobehavioral Cores for support of behavioral experiments and neurochemical analyses. Financial support for this work derives from the Postdoctoral Training Program in Functional Neurogenomics MH065215 (AS), NARSAD Young Investigator Grant from the BBRF (AS), a Max Kade fellowship from the Austrian Academy of Sciences (FPM), and NIH awards MH107132 (GLD), 2P20GM104360 (RAV) and MH086530 (RDB). RP and AEW received grant support from the Office for Undergraduate Research and Inquiry (OURI) at FAU.

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  1. Department of Biomedical Science, Florida Atlantic University, Jupiter, FL, USA

    Adele Stewart, Felix P. Mayer, Raajaram Gowrishankar, Gwynne L. Davis, Lorena B. Areal, Paul J. Gresch, Rania M. Katamish, Samantha E. Stilley, Keeley Spiess, Maximilian J. Rabil, Angelica E. Wiggins, Maureen K. Hahn & Randy D. Blakely

  2. Stiles-Nicholson Brain Institute, Florida Atlantic University, Jupiter, FL, USA

    Adele Stewart, Paul J. Gresch, Maureen K. Hahn & Randy D. Blakely

  3. Wilkes Honors College, Florida Atlantic University, Jupiter, FL, USA

    Rodeania Peart & Faakhira A. Diljohn

  4. Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA

    Roxanne A. Vaughan

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Contributions

AS and RDB conceived and designed experiments. FPM and RG performed slice biotinylation and pT53 pull down experiments. RG performed chronoamperometry. PJG performed surgeries and sample collection for microdialysis experiments and RMK performed HPLC analysis of dialysates. LBA performed the social interaction test. GLD performed the pERK immunoblotting experiment. AS performed all additional experiments with the assistance of RP, SES, KS, MJR, FAD, and AEW. RAV developed essential reagents. AS and RDB wrote the manuscript. M.K.H. aided in manuscript revision. All authors reviewed the manuscript prior to submission.

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Correspondence to Randy D. Blakely.

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Stewart, A., Mayer, F.P., Gowrishankar, R. et al. Behaviorally penetrant, anomalous dopamine efflux exposes sex and circuit dependent regulation of dopamine transporters. Mol Psychiatry 27, 4869–4880 (2022). https://doi.org/10.1038/s41380-022-01773-7

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