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The synthetic cathinones, butylone and pentylone, are stimulants that act as dopamine transporter blockers but 5-HT transporter substrates

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Abstract

Rationale

Synthetic cathinones continue to emerge in recreational drug markets worldwide. 1-(1,3-Benzodioxol-5-yl)-2-(methylamino)butan-1-one (butylone) and 1-(1,3-benzodioxol-5-yl)-2-(methylamino)pentan-1-one (pentylone) are derivatives of the cathinone compound, 1-(1,3-benzodioxol-5-yl)-2-(methylamino)propan-1-one (methylone), that are being detected in drug products and human casework.

Objectives

The purpose of the present study was to examine the neuropharmacology of butylone and pentylone using in vitro and in vivo methods.

Methods

In vitro uptake and release assays were carried out in rat brain synaptosomes and in cells expressing human dopamine transporters (DAT) and 5-HT transporters (SERT). In vivo microdialysis was performed in the nucleus accumbens of conscious rats to assess drug-induced changes in neurochemistry.

Results

Butylone and pentylone were efficacious uptake blockers at DAT and SERT, though pentylone was more DAT-selective. Both drugs acted as transporter substrates that evoked release of [3H]5-HT at SERT, while neither evoked release at DAT. Consistent with the release data, butylone and pentylone induced substrate-associated inward currents at SERT but not DAT. Administration of butylone or pentylone to rats (1 and 3 mg/kg, i.v.) increased extracellular monoamines and motor activity, but pentylone had weaker effects on 5-HT and stronger effects on motor stimulation.

Conclusions

Our data demonstrate that increasing the α-carbon chain length of methylone creates “hybrid” transporter compounds which act as DAT blockers but SERT substrates. Nevertheless, butylone and pentylone elevate extracellular dopamine and stimulate motor activity, suggesting both drugs possess significant risk for abuse.

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Acknowledgements

The authors acknowledge the generous funding of this project by the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Grant DA-00523 (MHB), and support by projects by the Austrian Science Fund/FWF (W1232 “MolTag” and F3506 to HHS).

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Authors and Affiliations

  1. Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Waehringerstrasse 13A, 1090, Vienna, Austria

    Kusumika Saha, Yang Li, Marion Holy, Walter Sandtner & Harald H. Sitte

  2. Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Sorbonne Paris Cité, 27 rue du Faubourg St-Jacques, 75014, Paris, France

    Kusumika Saha

  3. Designer Drug Research Unit (DDRU), Intramural Research Program (IRP), NIDA, NIH, DHHS, 333 Cassell Drive, Suite 4400, Baltimore, MD, 21224, USA

    Kurt R. Lehner, Mohammad O. Bukhari, John S. Partilla & Michael H. Baumann

  4. Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, MD, 21287, USA

    Kurt R. Lehner

  5. University of Pittsburgh Medical Center, Altoona, PA, 16601, USA

    Mohammad O. Bukhari

  6. Center for Addiction Research and Science, Medical University Vienna, Waehringerstrasse 13A, 1090, Vienna, Austria

    Harald H. Sitte

Authors
  1. Kusumika Saha
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  2. Yang Li
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  3. Marion Holy
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  9. Michael H. Baumann
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Contributions

MHB designed and oversaw in vitro and in vivo experiments in animals. JSP carried out uptake inhibition and release assays in synaptosomes, whereas KRL and MOB carried out microdialysis experiments in rats. HHS designed and oversaw experiments in HEK-293 cells transfected with human DAT and SERT. KS, YL, MH, and WS carried out experiments in transfected cells. MHB and HHS analyzed data. KS and MHB wrote the first draft of the paper, and all other authors contributed significantly to the writing of the final manuscript.

Corresponding author

Correspondence to Michael H. Baumann.

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Conflict of interest

H.H.S. has received honoraria for lectures and consulting from Lundbeck, Ratiopharm, Roche, Sanofi-Aventis, Serumwerk Bernburg. The remaining authors have no conflict of interest to report.

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This article belongs to a Special Issue on Bath Salts.

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Saha, K., Li, Y., Holy, M. et al. The synthetic cathinones, butylone and pentylone, are stimulants that act as dopamine transporter blockers but 5-HT transporter substrates. Psychopharmacology 236, 953–962 (2019). https://doi.org/10.1007/s00213-018-5075-5

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  • DOI: https://doi.org/10.1007/s00213-018-5075-5

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