{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T16:22:08Z","timestamp":1778170928405,"version":"3.51.4"},"reference-count":45,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,9]],"date-time":"2022-06-09T00:00:00Z","timestamp":1654732800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kent State University, the Applied Psychology Center in the Department of Psychological Sciences at Kent State University","award":["26249"],"award-info":[{"award-number":["26249"]}]},{"name":"2017 NARSAD Young Investigator Grant","award":["26249"],"award-info":[{"award-number":["26249"]}]},{"name":"Vital Projects Fund, Inc. (USA)","award":["26249"],"award-info":[{"award-number":["26249"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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\u2013600-fold less affinity. A considerable challenge in understanding PMAT\u2019s monoamine clearance contributions is that no current drugs selectively inhibit PMAT. To advance knowledge about PMAT\u2019s 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\u2019s 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.<\/jats:p>","DOI":"10.3390\/cells11121874","type":"journal-article","created":{"date-parts":[[2022,6,9]],"date-time":"2022-06-09T10:49:14Z","timestamp":1654771754000},"page":"1874","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Uncovering Functional Contributions of PMAT (Slc29a4) to Monoamine Clearance Using Pharmacobehavioral Tools"],"prefix":"10.3390","volume":"11","author":[{"given":"Jasmin N.","family":"Beaver","sequence":"first","affiliation":[{"name":"Department of Psychological Sciences & Brain Health Research Institute, Kent State University, Kent, OH 44242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brady L.","family":"Weber","sequence":"additional","affiliation":[{"name":"Department of Psychological Sciences & Brain Health Research Institute, Kent State University, Kent, OH 44242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0309-2900","authenticated-orcid":false,"given":"Matthew T.","family":"Ford","sequence":"additional","affiliation":[{"name":"Department of Psychological Sciences & Brain Health Research Institute, Kent State University, Kent, OH 44242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna E.","family":"Anello","sequence":"additional","affiliation":[{"name":"Department of Psychological Sciences & Brain Health Research Institute, Kent State University, Kent, OH 44242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah K.","family":"Kassis","sequence":"additional","affiliation":[{"name":"Department of Psychological Sciences & Brain Health Research Institute, Kent State University, Kent, OH 44242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8398-0195","authenticated-orcid":false,"given":"T. Lee","family":"Gilman","sequence":"additional","affiliation":[{"name":"Department of Psychological Sciences & Brain Health Research Institute, Kent State University, Kent, OH 44242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"12.16.1\u201312.16.17","DOI":"10.1002\/cpph.32","article-title":"Overview of Monoamine Transporters","volume":"79","author":"Aggarwal","year":"2017","journal-title":"Curr. Protoc. Pharm."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.pharmthera.2008.10.004","article-title":"Unfaithful neurotransmitter transporters: Focus on serotonin uptake and implications for antidepressant efficacy","volume":"121","author":"Daws","year":"2009","journal-title":"Pharm. Ther."},{"key":"ref_3","first-page":"119","article-title":"Organic Cation Transporters in the Central Nervous System","volume":"266","year":"2021","journal-title":"Handb. Exp. Pharm."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/164_2021_469","article-title":"The Interaction of Organic Cation Transporters 1-3 and PMAT with Psychoactive Substances","volume":"266","author":"Maier","year":"2021","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7124","DOI":"10.1016\/S0021-9258(17)37256-3","article-title":"Stable expression of biogenic amine transporters reveals differences in inhibitor sensitivity, kinetics, and ion dependence","volume":"269","author":"Gu","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1002\/cpt.442","article-title":"The plasma membrane monoamine transporter (PMAT): Structure, function, and role in organic cation disposition","volume":"100","author":"Wang","year":"2016","journal-title":"Clin. Pharm. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.jchemneu.2016.09.006","article-title":"Interspecies comparison of the functional characteristics of plasma membrane monoamine transporter (PMAT) between human, rat and mouse","volume":"83","author":"Shirasaka","year":"2017","journal-title":"J. Chem. Neuroanat."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.1038\/s41386-018-0053-5","article-title":"An unsuspected role for organic cation transporter 3 in the actions of amphetamine","volume":"43","author":"Mayer","year":"2018","journal-title":"Neuropsychopharmacology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1016\/j.neuroscience.2007.01.072","article-title":"Expression and immunolocalization of the plasma membrane monoamine transporter in the brain","volume":"146","author":"Dahlin","year":"2007","journal-title":"Neuroscience"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1124\/jpet.110.170142","article-title":"Selective Transport of Monoamine Neurotransmitters by Human Plasma Membrane Monoamine Transporter and Organic Cation Transporter 3","volume":"335","author":"Duan","year":"2010","journal-title":"J. Pharm. Exp. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.bmcl.2012.10.089","article-title":"A rhodamine-labeled citalopram analogue as a high-affinity fluorescent probe for the serotonin transporter","volume":"23","author":"Zhang","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1007\/s00213-005-0174-5","article-title":"MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: Implications for MDMA-induced neurotoxicity and treatment","volume":"189","author":"Verrico","year":"2007","journal-title":"Psychopharmacology"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Angenoorth, T.J., Stankovic, S., Niello, M., Holy, M., Brandt, S.D., Sitte, H.H., and Maier, J. (2021). Interaction Profiles of Central Nervous System Active Drugs at Human Organic Cation Transporters 1\u20133 and Human Plasma Membrane Monoamine Transporter. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222312995"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Clauss, N.J., Koek, W., and Daws, L.C. (2021). Role of Organic Cation Transporter 3 and Plasma Membrane Monoamine Transporter in the Rewarding Properties and Locomotor Sensitizing Effects of Amphetamine in Male and Female Mice. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222413420"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1097\/00008877-200209000-00014","article-title":"Cocaine sensitization in the mouse using a cumulative dosing regime","volume":"13","author":"Elliot","year":"2002","journal-title":"Behav. Pharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.pbb.2008.11.002","article-title":"Sensitivity to cocaine conditioned reward depends on sex and age","volume":"92","author":"Zakharova","year":"2009","journal-title":"Pharm. Biochem. Behav."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.pbb.2006.12.018","article-title":"Sex differences in (+)-amphetamine- and (+)-methamphetamine-induced behavioral response in male and female Sprague-Dawley rats","volume":"86","author":"McMillan","year":"2007","journal-title":"Pharm. Biochem. Behav."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1002\/jnr.23963","article-title":"Sex differences, gender and addiction: Sex, Gender, and Addiction","volume":"95","author":"Becker","year":"2016","journal-title":"J. Neurosci. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e14395","DOI":"10.14814\/phy2.14395","article-title":"Deletion of murine slc29a4 modifies vascular responses to adenosine and 5-hydroxytryptamine in a sexually dimorphic manner","volume":"8","author":"Wei","year":"2020","journal-title":"Physiol. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1111\/ejn.13968","article-title":"Constitutive plasma membrane monoamine transporter (PMAT, Slc29a4) deficiency subtly affects anxiety-like and coping behaviours","volume":"48","author":"Gilman","year":"2018","journal-title":"Eur. J. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3535","DOI":"10.1074\/jbc.M112.436972","article-title":"Impaired Monoamine and Organic Cation Uptake in Choroid Plexus in Mice with Targeted Disruption of the Plasma Membrane Monoamine Transporter (Slc29a4) Gene","volume":"288","author":"Duan","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_22","unstructured":"National Research Council (2011). Guide for the Care and Use of Laboratory Animals, National Academies Press. [8th ed.]."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S0166-4328(03)00034-2","article-title":"Antidepressant-like effects in various mice strains in the tail suspension test","volume":"143","author":"Ripoll","year":"2003","journal-title":"Behav. Brain Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1124\/jpet.116.233338","article-title":"Ontogeny of SERT Expression and Antidepressant-like Response to Escitalopram in Wild-Type and SERT Mutant Mice","volume":"358","author":"Mitchell","year":"2016","journal-title":"J. Pharm. Exp. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1038\/1841675b0","article-title":"The Principles of Humane Experimental Technique","volume":"184","author":"Russell","year":"1959","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/0165-0173(86)90002-0","article-title":"Enduring changes in brain and behavior produced by chronic amphetamine administration: A review and evaluation of animal models of amphetamine psychosis","volume":"11","author":"Robinson","year":"1986","journal-title":"Brain Res. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.neulet.2007.09.011","article-title":"Bimodal effect of amphetamine on motor behaviors in C57BL\/6 mice","volume":"427","author":"Yates","year":"2007","journal-title":"Neurosci. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s00213-009-1690-5","article-title":"Restoration of amphetamine-induced locomotor sensitization in dopamine D1 receptor-deficient mice","volume":"207","author":"Fan","year":"2010","journal-title":"Psychopharmacology"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Han, D.D., and Gu, H.H. (2006). Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs. BMC Pharm., 6.","DOI":"10.1186\/1471-2210-6-6"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s00210-009-0479-8","article-title":"Interaction of the human plasma membrane monoamine transporter (hPMAT) with antidepressants and antipsychotics","volume":"381","author":"Haenisch","year":"2010","journal-title":"Naunyn-Schmiedeberg\u2019s Arch. Pharm."},{"key":"ref_31","first-page":"339","article-title":"Do Outcomes of Clinical Trials Resemble Those \u201cReal World\u201d Patients? A Reanalysis of the STAR*D Antidepressant Data Set","volume":"5","author":"Kirsch","year":"2018","journal-title":"Psychol. Conscious Theory Res. Pract."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1001\/jamapsychiatry.2017.0025","article-title":"Reevaluating the Efficacy and Predictability of Antidepressant Treatments: A Symptom Clustering Approach","volume":"74","author":"Chekroud","year":"2017","journal-title":"JAMA Psychiatry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1177\/2045125316629071","article-title":"Bupropion: A systematic review and meta-analysis of effectiveness as an antidepressant","volume":"6","author":"Patel","year":"2016","journal-title":"Ther. Adv. Psychopharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1111\/bcp.12312","article-title":"Pharmacogenomics in psychiatry: The relevance of receptor and transporter polymorphisms","volume":"77","author":"Reynolds","year":"2014","journal-title":"Br. J. Clin. Pharm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.euroneuro.2011.10.003","article-title":"Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy","volume":"22","author":"Porcelli","year":"2012","journal-title":"Eur. Neuropsychopharm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"531","DOI":"10.3109\/08039488.2015.1012554","article-title":"SERT and NET polymorphisms, temperament and antidepressant response","volume":"69","author":"Andre","year":"2015","journal-title":"Nord. J. Psychiatry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1097\/FPC.0b013e32834c0010","article-title":"The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c","volume":"21","author":"Christensen","year":"2011","journal-title":"Pharm. Genom."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Moeez, S., Khalid, S., Shaeen, S., Khalid, M., Zia, A., Gul, A., Niazi, R., and Khalid, Z. (2021). Clinically significant findings of high-risk mutations in human SLC29A4 gene associated with diabetes mellitus type 2 in Pakistani population. J. Biomol. Struct. Dyn., 1\u201314.","DOI":"10.1080\/07391102.2021.1975561"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"dc182182","DOI":"10.2337\/dc18-2182","article-title":"Variation in the Plasma Membrane Monoamine Transporter (PMAT, Encoded in SLC29A4) and Organic Cation Transporter 1 (OCT1, Encoded in SLC22A1) and Gastrointestinal Intolerance to Metformin in Type 2 Diabetes: An IMI DIRECT Study","volume":"42","author":"Dawed","year":"2019","journal-title":"Diabetes Care"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1176\/appi.ajp.2011.11020191","article-title":"A Critical Review of the First 10 Years of Candidate Gene-by-Environment Interaction Research in Psychiatry","volume":"168","author":"Duncan","year":"2011","journal-title":"Am. J. Psychiatry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1002\/ajmg.10649","article-title":"DRD4 and novelty seeking: Results of meta-analyses","volume":"114","author":"Schinka","year":"2002","journal-title":"Am. J. Med. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s00439-009-0694-x","article-title":"Candidate gene studies of ADHD: A meta-analytic review","volume":"126","author":"Gizer","year":"2009","journal-title":"Hum. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1021\/acschemneuro.7b00042","article-title":"The Rodent Forced Swim Test Measures Stress-Coping Strategy, Not Depression-Like Behavior","volume":"8","author":"Commons","year":"2017","journal-title":"ACS Chem. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0361-9230(00)00313-0","article-title":"Central circuits mediating patterned autonomic activity during active vs. passive emotional coping","volume":"53","author":"Bandler","year":"2000","journal-title":"Brain Res. Bull."},{"key":"ref_45","first-page":"6503162","article-title":"Coping with the Forced Swim Stressor: Towards Understanding an Adaptive Mechanism","volume":"2016","author":"Molendijk","year":"2016","journal-title":"Neural Plast."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/12\/1874\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:27:01Z","timestamp":1760138821000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/12\/1874"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,9]]},"references-count":45,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["cells11121874"],"URL":"https:\/\/doi.org\/10.3390\/cells11121874","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,9]]}}}