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Dimethyltryptamine and other hallucinogenic tryptamines exhibit substrate behavior at the serotonin

Dimethyltryptamine and other hallucinogenic tryptamines exhibit substrate behavior at the serotonin

  1. Terrapinzflyer
    Dimethyltryptamine and other hallucinogenic tryptamines exhibit substrate behavior at the serotonin uptake transporter and the vesicle monoamine transporter
    Nicholas V. Cozzi Æ Anupama Gopalakrishnan Æ Lyndsey L. Anderson Æ Joel T. Feih Æ Alexander T. Shulgin Æ Paul F. Daley Æ Arnold E. Ruoho

    Received: 11 May 2009 / Accepted: 24 August 2009 Ó Springer-Verlag 2009

    Abstract N,N-dimethyltryptamine (DMT) is a potent plant hallucinogen that has also been found in human tissues. When ingested, DMT and related N,N-dialkyltryptamines produce an intense hallucinogenic state. Behavioral effects are mediated through various neurochemical mechanisms including activity at sigma-1 and serotonin receptors, modification of monoamine uptake and release, and competition for metabolic enzymes. To further clarify the pharmacology of hallucinogenic tryptamines, we synthesized DMT, N-methyl-N-isopropyltryptamine (MIPT), N,N-dipropyltryptamine (DPT), and N,N-diisopropyltryptamine. We then tested the abilities of these N,N-dialkyltryptamines to inhibit [3H]5-HT uptake via the plasma membrane serotonin transporter (SERT) in human platelets and via the vesicle monoamine transporter (VMAT2) in Sf9 cells expressing the rat VMAT2. The tryptamines were also tested as inhibitors of [3H]paroxetine binding to the SERT and [3H]dihydrotetrabenazine binding to VMAT2. Our results show that DMT, MIPT, DPT, and DIPT inhibit [3H]5-HT transport at the SERT with KI values of 4.00 ± 0.70, 8.88 ± 4.7, 0.594 ± 0.12, and 2.32 ±

    0.46 lM, respectively. At VMAT2, the tryptamines inhibited [3H]5-HT transport with KI values of 93 ± 6.8, 20 ± 4.3, 19 ± 2.3, and 19 ± 3.1 lM, respectively. On the other hand, the tryptamines were very poor inhibitors of [3H]paroxetine binding to SERT and of [3H]dihydrotetrabenazine binding to VMAT2, resulting in high binding-touptake ratios. High binding-to-uptake ratios support the hypothesis that the tryptamines are transporter substrates, not uptake blockers, at both SERT and VMAT2, and also indicate that there are separate substrate and inhibitor binding sites within these transporters. The transporters may allow the accumulation of tryptamines within neurons to reach relatively high levels for sigma-1 receptor activation and to function as releasable transmitters. Keywords Biogenic amine Á Dihydrotetrabenazine Á Dimethyltryptamine Á DMT Á Dipropyltryptamine Á DPT Á Diisopropyltryptamine Á DIPT Á Methylisopropyltryptamine Á MIPT Á Psychedelic Á Paroxetine Á Serotonin Á Sigma-1 receptor Á Tetrabenazine