Journal article
Behaviorally penetrant, anomalous dopamine efflux exposes sex and circuit dependent regulation of dopamine transporters
Molecular psychiatry, Vol.27(12), pp.4869-4880
12/01/2022
DOI: 10.1038/s41380-022-01773-7
PMCID: PMC12784422
PMID: 36117213
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.
Details
- Title: Subtitle
- Behaviorally penetrant, anomalous dopamine efflux exposes sex and circuit dependent regulation of dopamine transporters
- Creators
- Adele Stewart - Florida Atlantic UniversityFelix P Mayer - Florida Atlantic UniversityRaajaram Gowrishankar - Florida Atlantic UniversityGwynne L Davis - Florida Atlantic UniversityLorena B Areal - Florida Atlantic UniversityPaul J Gresch - Florida Atlantic UniversityRania M Katamish - Florida Atlantic UniversityRodeania Peart - Florida Atlantic UniversitySamantha E Stilley - Florida Atlantic UniversityKeeley Spiess - Florida Atlantic UniversityMaximilian J Rabil - Florida Atlantic UniversityFaakhira A Diljohn - Florida Atlantic UniversityAngelica E Wiggins - Florida Atlantic UniversityRoxanne A Vaughan - University of North DakotaMaureen K Hahn - Florida Atlantic UniversityRandy D Blakely - Florida Atlantic University
- Resource Type
- Journal article
- Publication Details
- Molecular psychiatry, Vol.27(12), pp.4869-4880
- DOI
- 10.1038/s41380-022-01773-7
- PMID
- 36117213
- PMCID
- PMC12784422
- NLM abbreviation
- Mol Psychiatry
- ISSN
- 1359-4184
- eISSN
- 1476-5578
- Grant note
- MH086530 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) MH065215 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) MH107132 / U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH) 2P20GM104360 / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
- Language
- English
- Date published
- 12/01/2022
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9984618523502771
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