Kusumika Saha1,2, Yang Li1, Marion Holy1, Kurt R Lehner3,4, Mohammad O Bukhari3,5, John S Partilla3, Walter Sandtner1, Harald H Sitte1,6, Michael H Baumann7. 1. Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Waehringerstrasse 13A, 1090, Vienna, Austria. 2. Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Descartes, Sorbonne Paris Cité, 27 rue du Faubourg St-Jacques, 75014, Paris, France. 3. Designer Drug Research Unit (DDRU), Intramural Research Program (IRP), NIDA, NIH, DHHS, 333 Cassell Drive, Suite 4400, Baltimore, MD, 21224, USA. 4. Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, MD, 21287, USA. 5. University of Pittsburgh Medical Center, Altoona, PA, 16601, USA. 6. Center for Addiction Research and Science, Medical University Vienna, Waehringerstrasse 13A, 1090, Vienna, Austria. 7. Designer Drug Research Unit (DDRU), Intramural Research Program (IRP), NIDA, NIH, DHHS, 333 Cassell Drive, Suite 4400, Baltimore, MD, 21224, USA. mbaumann@mail.nih.gov.
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.
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.
Authors: Michael H Baumann; Mario A Ayestas; John S Partilla; Jacqueline R Sink; Alexander T Shulgin; Paul F Daley; Simon D Brandt; Richard B Rothman; Arnold E Ruoho; Nicholas V Cozzi Journal: Neuropsychopharmacology Date: 2011-12-14 Impact factor: 7.853
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