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"Polytox" synthetic cathinone abuse: A potential role for organic cation transporter 3 in combined cathinone-induced efflux.
Neurochem Int. 2019 02; 123:7-12.NI

Abstract

Synthetic cathinone derivatives are a new class of psychoactive substances (NPS), also known as "bath salts", designed to exert psychostimulant effects resembling those of well-known psychostimulants, such as cocaine and 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). As major constituents of bath salts, the cathinone derivatives 3,4-methylenedioxypyrovalerone (MDPV) and 4-methylmethcathinone (mephedrone), have received considerable media attention. MDPV and mephedrone interfere with the function of the high affinity transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT), resulting in increased extracellular levels of these monoamines, though their mechanism of action differs. MDPV acts as a non-transported inhibitor of DAT, NET and SERT, whereas mephedrone promotes transporter-mediated release in an amphetamine-like fashion. MDPV and mephedrone are often taken together, creating a conundrum in as much as non-transported inhibitors, like MDPV, prevent mephedrone-induced reverse transport via DAT, NET and SERT. Here we provide evidence supporting a role for organic cation transporter 3 (OCT3) in the actions of mephedrone, which may account for its ability to enhance effects of MDPV. We show that mephedrone can induce substrate efflux via OCT3 in the presence of MDPV. Real-time recordings of the fluorescent OCT3 substrate (4-(4-dimethylamino)styryl)-N-methylpyridinium (ASP+) and radiotracer-flux studies using [3H]1-methyl-4-phenyl-pyridinium (MPP+), demonstrated that OCT3 is MDPV-insensitive when expressed in human embryonic kidney (HEK293) cells. Ex vivo experiments performed in cultured superior cervical ganglia (SCG) cells, rich in NET and OCT3, revealed that mephedrone induces [3H]MPP+ release in an OCT3-dependent manner when NET is fully occupied with MDPV. These results extend our recent findings that OCT3 is key in the mechanism of action of amphetamine-induced substrate release. OCT3 likewise appears to be a mechanism through which mephedrone can induce release of monoamines, thereby accounting for the paradoxically more potent psychostimulant effects of MDPV taken together with mephedrone, and greater risk for deleterious side effects.

Authors+Show Affiliations

Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Waehringer Straβe 13A, 1090, Vienna, Austria.Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Waehringer Straβe 13A, 1090, Vienna, Austria.Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Waehringer Straβe 13A, 1090, Vienna, Austria.Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA; Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Waehringer Straβe 13A, 1090, Vienna, Austria; Center for Addiction Research and Science, Medical University Vienna, Waehringerstrasse 13 A, 1090, Vienna, Austria. Electronic address: harald.sitte@meduniwien.ac.at.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30248432

Citation

Mayer, Felix P., et al. ""Polytox" Synthetic Cathinone Abuse: a Potential Role for Organic Cation Transporter 3 in Combined Cathinone-induced Efflux." Neurochemistry International, vol. 123, 2019, pp. 7-12.
Mayer FP, Schmid D, Holy M, et al. "Polytox" synthetic cathinone abuse: A potential role for organic cation transporter 3 in combined cathinone-induced efflux. Neurochem Int. 2019;123:7-12.
Mayer, F. P., Schmid, D., Holy, M., Daws, L. C., & Sitte, H. H. (2019). "Polytox" synthetic cathinone abuse: A potential role for organic cation transporter 3 in combined cathinone-induced efflux. Neurochemistry International, 123, 7-12. https://doi.org/10.1016/j.neuint.2018.09.008
Mayer FP, et al. "Polytox" Synthetic Cathinone Abuse: a Potential Role for Organic Cation Transporter 3 in Combined Cathinone-induced Efflux. Neurochem Int. 2019;123:7-12. PubMed PMID: 30248432.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - "Polytox" synthetic cathinone abuse: A potential role for organic cation transporter 3 in combined cathinone-induced efflux. AU - Mayer,Felix P, AU - Schmid,Diethart, AU - Holy,Marion, AU - Daws,Lynette C, AU - Sitte,Harald H, Y1 - 2018/09/21/ PY - 2018/07/26/received PY - 2018/09/14/revised PY - 2018/09/19/accepted PY - 2018/9/25/pubmed PY - 2019/12/27/medline PY - 2018/9/25/entrez KW - Cathinones KW - Dopamine transporter KW - Monoamines KW - Organic cation transporter 3 KW - Psychostimulant SP - 7 EP - 12 JF - Neurochemistry international JO - Neurochem. Int. VL - 123 N2 - Synthetic cathinone derivatives are a new class of psychoactive substances (NPS), also known as "bath salts", designed to exert psychostimulant effects resembling those of well-known psychostimulants, such as cocaine and 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). As major constituents of bath salts, the cathinone derivatives 3,4-methylenedioxypyrovalerone (MDPV) and 4-methylmethcathinone (mephedrone), have received considerable media attention. MDPV and mephedrone interfere with the function of the high affinity transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT), resulting in increased extracellular levels of these monoamines, though their mechanism of action differs. MDPV acts as a non-transported inhibitor of DAT, NET and SERT, whereas mephedrone promotes transporter-mediated release in an amphetamine-like fashion. MDPV and mephedrone are often taken together, creating a conundrum in as much as non-transported inhibitors, like MDPV, prevent mephedrone-induced reverse transport via DAT, NET and SERT. Here we provide evidence supporting a role for organic cation transporter 3 (OCT3) in the actions of mephedrone, which may account for its ability to enhance effects of MDPV. We show that mephedrone can induce substrate efflux via OCT3 in the presence of MDPV. Real-time recordings of the fluorescent OCT3 substrate (4-(4-dimethylamino)styryl)-N-methylpyridinium (ASP+) and radiotracer-flux studies using [3H]1-methyl-4-phenyl-pyridinium (MPP+), demonstrated that OCT3 is MDPV-insensitive when expressed in human embryonic kidney (HEK293) cells. Ex vivo experiments performed in cultured superior cervical ganglia (SCG) cells, rich in NET and OCT3, revealed that mephedrone induces [3H]MPP+ release in an OCT3-dependent manner when NET is fully occupied with MDPV. These results extend our recent findings that OCT3 is key in the mechanism of action of amphetamine-induced substrate release. OCT3 likewise appears to be a mechanism through which mephedrone can induce release of monoamines, thereby accounting for the paradoxically more potent psychostimulant effects of MDPV taken together with mephedrone, and greater risk for deleterious side effects. SN - 1872-9754 UR - https://www.unboundmedicine.com/medline/citation/30248432/"Polytox"_synthetic_cathinone_abuse:_A_potential_role_for_organic_cation_transporter_3_in_combined_cathinone_induced_efflux_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0197-0186(18)30343-7 DB - PRIME DP - Unbound Medicine ER -