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Article

Uncovering Functional Contributions of PMAT (Slc29a4) to Monoamine Clearance Using Pharmacobehavioral Tools

Department of Psychological Sciences & Brain Health Research Institute, Kent State University, Kent, OH 44242, USA
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Academic Editors: Sonja Sucic, Lynette C. Daws, Ameya Sanjay Kasture and Shreyas Bhat
Cells 2022, 11(12), 1874; https://doi.org/10.3390/cells11121874
Received: 11 May 2022 / Revised: 1 June 2022 / Accepted: 7 June 2022 / Published: 9 June 2022
(This article belongs to the Special Issue Neurotransmitter Transporters in Health and Disease)
Plasma membrane monoamine transporter (PMAT, Slc29a4) transports monoamine neurotransmitters, including dopamine and serotonin, faster than more studied monoamine transporters, e.g., dopamine transporter (DAT), or serotonin transporter (SERT), but with ~400–600-fold less affinity. A considerable challenge in understanding PMAT’s monoamine clearance contributions is that no current drugs selectively inhibit PMAT. To advance knowledge about PMAT’s monoamine uptake role, and to circumvent this present challenge, we investigated how drugs that selectively block DAT/SERT influence behavioral readouts in PMAT wildtype, heterozygote, and knockout mice of both sexes. Drugs typically used as antidepressants (escitalopram, bupropion) were administered acutely for readouts in tail suspension and locomotor tests. Drugs with psychostimulant properties (cocaine, D-amphetamine) were administered repeatedly to assess initial locomotor responses plus psychostimulant-induced locomotor sensitization. Though we hypothesized that PMAT-deficient mice would exhibit augmented responses to antidepressant and psychostimulant drugs due to constitutively attenuated monoamine uptake, we instead observed sex-selective responses to antidepressant drugs in opposing directions, and subtle sex-specific reductions in psychostimulant-induced locomotor sensitization. These results suggest that PMAT functions differently across sexes, and support hypotheses that PMAT’s monoamine clearance contribution emerges when frontline transporters (e.g., DAT, SERT) are absent, saturated, and/or blocked. Thus, known human polymorphisms that reduce PMAT function could be worth investigating as contributors to varied antidepressant and psychostimulant responses. View Full-Text
Keywords: sex differences; psychostimulants; antidepressants; tail suspension test; locomotor activity; monoamine transporters; sensitization sex differences; psychostimulants; antidepressants; tail suspension test; locomotor activity; monoamine transporters; sensitization
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MDPI and ACS Style

Beaver, J.N.; Weber, B.L.; Ford, M.T.; Anello, A.E.; Kassis, S.K.; Gilman, T.L. Uncovering Functional Contributions of PMAT (Slc29a4) to Monoamine Clearance Using Pharmacobehavioral Tools. Cells 2022, 11, 1874. https://doi.org/10.3390/cells11121874

AMA Style

Beaver JN, Weber BL, Ford MT, Anello AE, Kassis SK, Gilman TL. Uncovering Functional Contributions of PMAT (Slc29a4) to Monoamine Clearance Using Pharmacobehavioral Tools. Cells. 2022; 11(12):1874. https://doi.org/10.3390/cells11121874

Chicago/Turabian Style

Beaver, Jasmin N., Brady L. Weber, Matthew T. Ford, Anna E. Anello, Sarah K. Kassis, and T. L. Gilman. 2022. "Uncovering Functional Contributions of PMAT (Slc29a4) to Monoamine Clearance Using Pharmacobehavioral Tools" Cells 11, no. 12: 1874. https://doi.org/10.3390/cells11121874

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