Top

Published in:

Open Access 01-11-2016 | Original Article

Neurotoxic Effects of 5-MeO-DIPT: A Psychoactive Tryptamine Derivative in Rats

Authors: Karolina Noworyta-Sokołowska, Katarzyna Kamińska, Grzegorz Kreiner, Zofia Rogóż, Krystyna Gołembiowska

Published in: Neurotoxicity Research | Issue 4/2016

Abstract

5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT, ‘foxy’) is one of the most popular tryptamine hallucinogens in the illicit drug market. It produces serious adverse effects, but its pharmacological profile is not well recognized. In vitro data have shown that 5-MeO-DIPT acts as a potent serotonin transporter (SERT) inhibitor and displays high affinity at serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors. In this study, using microdialysis in freely moving rats, we examined the effect of 5-MeO-DIPT on dopamine (DA), serotonin (5-HT), and glutamate release in the rat striatum, nucleus accumbens, and frontal cortex. In search of a possible neurotoxic effect of 5-MeO-DIPT, we measured DA and 5-HT tissue content in the above rat brain regions and also determined the oxidative DNA damage with the comet assay. Moreover, we tested drug-elicited head-twitch response and a forepaw treading induced by 8-OH-DPAT. 5-MeO-DIPT at doses of 5, 10, and 20 mg/kg increased extracellular DA, 5-HT, and glutamate level but the differences in the potency were found between brain regions. 5-MeO-DIPT increased 5-HT and decreased 5-HIAA tissue content which seems to result from SERT inhibition. On the other hand, a decrease in DA, DOPAC, and HVA tissue contents suggests possible adaptive changes in DA turnover or damage of DA terminals by 5-MeO-DIPT. DNA single and double-strand breaks persisted up to 60 days after the treatment, indicating marked neurotoxicity of 5-MeO-DIPT. The induction of head-twitch response and potentiation of forepaw treading induced by 8-OH-DPAT indicate that hallucinogenic activity seems to be mediated through the stimulation of 5-HT2A and 5-HT1A receptors by 5-MeO-DIPT.

Aghajanian GH, Marek GJ (1997) Serotonin induces excitatory postsynaptic in apical dendrites of neocortical pyramidal cells. Neuropsychopharmacology 36:589–599

Aghajanian GH, Marek GJ (1999) Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release. Brain Res 825:161–171CrossRefPubMed

Araneda R, Andrade R (1991) 5-hydroxytryptamine 2 and 5-hydroxytryptamine 1A receptors mediate opposing responses on membrane excitability in rat association cortex. Neuroscience 40:399–412CrossRefPubMed

Beique JC, Imad M, Mladenovic L, Gingrich JA, Andrade R (2007) Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex. Proc Natl Acad Sci USA 104:9870–9875CrossRefPubMedPubMedCentral

Blough BE, Landavazo A, Decker AM, Partilla JS, Baumann MH, Rothman RB (2014) Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes. Psychopharmacology 231:4135–4144CrossRefPubMedPubMedCentral

Celada P, Puig MV, Casanovas JM, Guillazo G, Artigas F (2001) Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: involvement of serotonin-1A, GABA(A), and glutamate receptors. J Neurosci 21:9917–9929PubMed

Chambers JJ, Kurrasch-Orbaugh DM, Parker MA, Nichols DE (2001) Enantiospecific synthesis and pharmacological evaluation of a series of super-potent, conformationally restricted 5-HT(2A/2C) receptor agonists. J Med Chem 44:1003–1010CrossRefPubMed

Colpaert FC, Janssen PA (1983) A characterization of LSD-antagonist effects of pirenperone in the rat. Neuropharmacology 22:1001–1005CrossRefPubMed

Compton DM, Selinger MC, Westman E, Otero P (2011) Differentiation of MDMA or 5-MeO-DIPT induced cognitive deficits in rat following adolescent exposure. Psych Neurosci 4:157–169CrossRef

De Deurwaerdere P, Navailles S, Berg KA, Clarke WP, Spampinato U (2004) Constitutive activity of the serotonergic2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens. Neuroscience 24:3235–3241PubMed

deMontigny C, Aghajanian GK (1977) Preferential action of 5-methoxytryptamine and 5-methoxydimethyltryptamine on presynaptic serotonin receptors: a comparative iontophoretic study with LSD and serotonin. Neuropharmacology 16:811–818CrossRef

Di Matteo V, Di Giovanni G, Di Mascio M, Esposito E (1999) SB 242084, a selective serotonin2C receptor antagonist, increases dopaminergic transmission in the mesolimbic system. Neuropharmacology 38:1195–1205CrossRefPubMed

Drug Enforcement Administration, Office of Diversion Control, Drug and Chemical Evaluation Section, April 2013

Fahn S, Sulzer D (2004) Neurodegeneration and neuroprotection in Parkinson Disease. NeuroRx 1:139–154CrossRefPubMedPubMedCentral

Fantegrossi WE, Harrington AW, Kiessel CL, Eckler JR, Rabin JR, Winter JC, Coop A, Rice KC, Woods JH (2006) Hallucinogen-like actions of 5-methoxy-N, N-diisopropyltryptamine in mice and rats. Pharmacol Biochem Behav 83:122–129CrossRefPubMed

Fantegrossi WE, Somoneau J, Cohen MS, Zimmerman SM, Henson CM, Rice KC, Woods JH (2010) Interaction of 5-HT2A and 5-HT2C receptors in DOI-elicited head twitch behavior in mice. J Pharmacol Exp Ther 335:728–734CrossRefPubMedPubMedCentral

Frenzilli G, Ferrucci M, Giorgi FS, Blandini F, Nigro M, Ruggieri S, Murri L, Paparelli A, Fornai F (2007) DNA fragmentation and oxidative stress in the hippocampal formation: a bridge between 3,4-methylenedioxymethamphetamine (ecstasy) intake and long-lasting behavioral alterations. Behav Pharmacol 18:471–481CrossRefPubMed

Glennon RA, Titeler M, McKenney JD (1984) Evidence for 5HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sci 35:2505–2511CrossRefPubMed

González-Maeso J, Weisstaub NV, Zhou M, Chan P, Iviv L, Ang R, Lira A, Bradley-Moore M, Ge Y, Zhou Q, Sealfon SC, Gingrich JA (2007) Hallucinogens recruit specific cortical 5-HT2A receptor-mediated signaling pathways to affect behavior. Neuron 53:439–452CrossRefPubMed

Halberstadt AL (2015) Recent advances in the neuropsychopharmacology of serotonergic hallucinogens. Behav Brain Res 277:99–120CrossRefPubMed

Halberstadt AL, Geyer MA (2011) Multiple receptors contribute to the behavioral effects of indoloamine hallucinogens. Neuropharmacology 61:364–381CrossRefPubMedPubMedCentral

Halberstadt AL, van der Heijden I, Ruderman MA, Risbrough VB, Gingrich JA, Geyer MA, Powell SB (2009) 5-HT_2A and 5-HT_2C receptors exert opposing effects on locomotor activity in mice. Neuropsychopharmacol 34:1958–1967CrossRef

Halliwell B (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem 97:1634–1658CrossRefPubMed

Halliwell B, Whiteman M (2004) Measuring reactive species and oxidative damage in vivo and in cell culture: how should you do it and what do the results mean? Brit J Pharmacol 142:231–255CrossRef

Hamon M, Gozlan H, El Mestikawy S, Emerit MB, Bolanos AF, Schechter L (1990) The central 5-HT_1A receptors: pharmacological, biochemical, functional, and regulatory properties. Ann NY Acad Sci 600:114–129CrossRefPubMed

Johnson Z, Venters J, Guarraci FA, Zewail-Foote M (2015) Methamphetamine induces DNA damage in specific regions of the female rat brain. Clin Exp Pharmacol Physiol 42:570–575CrossRefPubMed

Kanamori T, Kuwayama K, Tsujikawa K, Miyaguchi H, Iwata Y, Inoue H, Kishi T (2006) In vivo metabolism of 5-Methoxy-NN-diisopropyltryptamine in rat. J Health Science 52:425–430CrossRef

Leysen JE, Niemegeers CJ, Van Nueten JM, Laduron PM (1982) [³H]Ketanserin (R 41 468), a selective ³H-ligand for serotonin₂ receptor binding sites. Binding properties, brain distribution, and functional role. Mol Pharmacol 21:301–314PubMed

Liu J, Head E, Gharib AM, Yuan W, Ingersoll RT, Hagen TM, Cotman CW, Ames BN (2002) memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-α-lipoic acid. Proc Natl Acad Sci USA 99:2356–2361CrossRefPubMedPubMedCentral

Lucas G, Spampinato U (2000) Role of striatal serotonin_2A and serotonin_2C receptor subtypes in the control of in vivo dopamine outflow in the rat striatum. J Neurochem 74:693–701CrossRefPubMed

Marquis KL, Sabb AL, Logue SF, Brennan JA, Piesla MJ, Comery TA, Grauer SM, Ashby CR Jr, Nguyen HQ, Dawson LA, Barret JE, Stack G, Meltzer HY, Harrison BL, Rosenzweig-Lipson S (2007) WAY-163909 [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,71hi]indole]:a novel 5-hydroxytryptamine 2C receptor-selective agonist with preclinical antipsychotic-like activity. J Pharmacol Exp Ther 320:486–496CrossRefPubMed

Martin-Ruiz R, Puig MV, Celada P, Shapiro DA, Roth BL, Mengod G, Artigas F (2001) Control of serotonergic function in medial prefrontal cortex by serotonin-2A receptors through a glutamate-dependent mechanism. J Neurosci 21:9856–9866PubMed

Muschamp JW, Regina MJ, Hull EM, Winter JC, Rabin RA (2004) Lysergic acid diethylamide and [-]-2,5-dimethoxy-4-methylamphetamine increase extracellular glutamate in rat prefrontal cortex. Brain Res 1023:134–140CrossRefPubMed

Nagai F, Nonaka R, Satoh K, Kamimura H (2007) The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain. Eur J Pharmacol 559:132–137CrossRefPubMed

Nakagawa T, Kaneko S (2008) Neuropsychotoxicity of abused drugs: molecular and neural mechanisms of neuropsychotoxicity induced by methamphetamine, 3,4-methylenedioxymethamphetamine (Ecstasy), and 5-Methoxy-N, N-diisopropyltryptamine (Foxy). J Pharmacol Sci 106:2–8CrossRefPubMed

Nelson DL, Lucaites VL, Wainscott DB, Glennon RA (1999) Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT_2A, 5-HT_2B and 5-HHT_2C receptors. Naunyn-Schmiedeberg’s Arch Pharmacol 359:1–6CrossRef

Nichols DE (1997) Role of serotonergic neurons and 5-HT receptors in the action of hallucinogens. In: Abumgarten HG, Goethert M (eds) Serotonergic Neurons and 5-HT Receptors in the CNS. Springer-Verlag, Berlin, pp 563–585

O’Brien CP (2001) Drug addiction and drug abuse. In: Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG (eds) Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 5-HT_2A heteroceptors on thalamocortical glutamatergic neurons. McGraw-Hill, New York, pp 8846–8852

Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. Academic Press, San Diego

Pazos A, Palacios JM (1985) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. I. serotonin-1 receptors. Brain Res 346:205–230CrossRefPubMed

Pehek EA, McFarlane HG, Maguschak K, Price B, Pluto CP (2001) M100,907, a selective 5-HT_2A antagonist, attenuates dopamine release in the rat medial prefrontal cortex. Brain Res 888:51–59CrossRefPubMed

Puig MV, Celada P, az-Mataix L, Artigas F (2003) In vivo modulation of the activity of pyramidal neurons in the rat medial prefrontal cortex by 5-HT2A receptors; relationship to thalamocortical afferents. Cereb Cortex 13:870–882CrossRefPubMed

Sakaue M, Somboonthum P, Nishihara B, Koyama Y, Hashimoto H, Baba A, Matsuda T (2000) Postsynaptic 5-Hydroxytryptamine_1A receptor activation increases in vivo dopamine release in rat prefrontal cortex. Brit J Pharmacol 129:1028–1034CrossRef

Sanchez C, Arnt J, Moltzen E (1996) Assesment of relative efficacies of 5-HT1A receptor ligands by means of in vivo animal modeles. Eur J Pharmacol 315:245–254CrossRefPubMed

Santana N, Bortolozzi A, Serrats J, Mengod G, Artigas F (2004) Expression of serotonina1A and serotonin2A receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex. Cereb Cortex 14:1100–1109CrossRefPubMed

Schreiber R, Brocco M, Audinot V, Gobert A, Veiga S, Millan MJ (1995) (1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane)-induced head-twitches in the rat are mediated by 5-hydroxytryptamine (5-HT) 2A receptors: modulation by novel 5-HT2A/2C antagonists, D1 antagonists and 5-HT1A agonists. J Pharmacol Exp Ther 273:101–112PubMed

Scruggs JL, Schmidt D, Deutch AY (2003) The hallucinogen 1-[2,5-dimethoxy-4-iodophenyl]-2-amoinopropane (DOI) increases cortical extracellular glutamate levels in rats. Neurosci Lett 346:137–140CrossRefPubMed

Shulgin AT, Carter MF (1980) N, N-Diisopropyltryptamine (DIPT) and 5-methoxy-N, N-diisopropyltryptamine (5-MeO-DIPT), two orally active tryptamine analogs with CNS activity. Comm Psychopharmacol 4:363–369

Sipes TE, Geyer MA (1995) DOI disruption of prepulse inhibition of startle in the rat is mediated by 5-HT2A and not by 5-HT2C receptors. Behav Pharnmacol 6:839–842

Skelton MR, Schaefer TL, Herring NR, Grace CE, Vorhees CV, Williams MT (2009) Comparison of the developmental effects of 5-methoxy-N, N-diisopropyltryptamine (Foxy) to (±)-3,4-methylenedioxymethamphetamine (ecstasy) in rats. Psychopharmacology 204:287–297CrossRefPubMedPubMedCentral

Sloviter RS, Drust EG, Connor JD (1978) Specificity of a rat behavioral model for serotonin receptor activation. J Pharmacol Exp Ther 206:339–347PubMed

Smith LM, Peroutka SJ (1986) Differential effects of 5-hydroxytryptamine 1a selective drugs on the 5-HT behavioral syndrome. Pharmacol Biochem Behav 24:1513–1519CrossRefPubMed

Smith RL, Canton H, Barret RJ, Sanders-Bush E (1998) Agonist properties of N, N-dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors. Pharmacol Biochem Behav 61:232–330CrossRef

Smith RL, Barret RJ, Sanders-Bush E (1999) Mechanism of tolerance development to 2,5-dimethoxy-4-iodoamphetamine in rats: down-regulation of the 5-HT_2A, but not 5-HT_2C, receptor. Psychopharmacol (Berl) 144:248–254CrossRef

Sogawa C, Sogawa N, Tagawa J, Fujino A, Ohyama K, Asanuma M, Funada M, Kitayama S (2007) 5-Methoxy-N, N-diisopropyltryptamine (Foxy), a selective and high affinity inhibitor of serotonin transporter. Toxicol Lett 170:75–82CrossRefPubMed

Tanda G, Caroni E, Frau R, Di Chiara G (1994) Increase of extracellular dopamine in the prefrontal cortex: a trait of drugs with antidepressant potential? Psychopharmacology 115:288CrossRef

Titeler M, Lyon RA, Glennon RA (1988) Radioligand binding evidence implicates the brain 5-HT₂ receptor as a site of action for LSD and phenylisopropylamine hallucinogens. Psychopharamcology (Berl) 94:213–216

Tittarelli R, Mannocchi G, Pantano F, Romolo FS (2015) Recreational use, analysis and toxicity of tryptamines. Curr Neuropharmacol 13:26–46CrossRefPubMedPubMedCentral

Vazquez-Borsetti P, Cortes R, Artigas F (2009) Pyramidal neurons in rat prefrontal cortex projecting to ventral tegmental area and dorsal raphe nucleus express 5-HT2A receptors. Cereb Cortex 19:1678–1686CrossRefPubMed

Vickers SP, Easton N, Malcolm CS, Allen NH, Porter RH, Bickerdike MJ et al (2001) Modulation of 5-HT2A receptor-mediated head-twitch behaviour in the rat by 5-HT2C receptor agonists. Pharmacol Biochem Behav 69:643–652CrossRefPubMed

Wędzony K, Maćkowiak M, Fijał K, Gołembiowska K (1996) Ipsapirone enhances the dopamine outflow via 5-HT_1A receptors in the rat prefrontal cortex. Eur J Pharmacol 305:73–78CrossRefPubMed

Wettstein JG, Host M, Hitchcock JM (1999) Selectivity of action of typical and atypical anti-psychotic drugs as antagonists of the behavioral effects of 1-[2,5-dimethoxy-4-iodophenyll]-2-aminopropane (DOI). Prog Neuropsychopharmacol Biol Psychiatry 23:533–544CrossRefPubMed

Williams MT, Herring NR, Schaefer TL, Skelton MR, Campbell NG, Lipton JW, McCrea AE, Vorhees CV (2007) Alterations in body temperature, corticosterone, and behavior following the administration of 5-methoxy-diisopropyltryptamine (‘Foxy’) to adult rats: a new drug of abuse. Neuropsychopharmacol 32:1404–1420CrossRef

Willins DL, Meltzer HY (1997) Direct injection of 5-HT_2A receptor agonists into the medial prefrontal cortex produces a head-twitch response in rats. J Pharmacol Exp Ther 282:699–706PubMed

Yan QS (2000) Activation of 5-HT_2A/2C receptors within the nucleus accumbens increases local dopaminergic transmission. Brain Res Bull 51:75–81CrossRefPubMed

Title: Neurotoxic Effects of 5-MeO-DIPT: A Psychoactive Tryptamine Derivative in Rats
Authors: Karolina Noworyta-Sokołowska
Katarzyna Kamińska
Grzegorz Kreiner
Zofia Rogóż
Krystyna Gołembiowska
Publication date: 01-11-2016
Publisher: Springer US
Published in: Neurotoxicity Research / Issue 4/2016
Print ISSN: 1029-8428
Electronic ISSN: 1476-3524
DOI: https://doi.org/10.1007/s12640-016-9654-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Neurotoxic Effects of 5-MeO-DIPT: A Psychoactive Tryptamine Derivative in Rats

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2016

Comparison of the Effects of Acute and Chronic Administration of Tetrahydroisoquinoline Amines on the In Vivo Dopamine Release: A Microdialysis Study in the Rat Striatum

Reactive Oxygen Species-mediated Loss of Phenotype of Parvalbumin Interneurons Contributes to Long-term Cognitive Impairments After Repeated Neonatal Ketamine Exposures

Characterization of the Kynurenine Pathway in CD8+ Human Primary Monocyte-Derived Dendritic Cells

Nanomedicine to Overcome Current Parkinson’s Treatment Liabilities: A Systematic Review

Hydroxyurea Treatment and Development of the Rat Cerebellum: Effects on the Neurogenetic Profiles and Settled Patterns of Purkinje Cells and Deep Cerebellar Nuclei Neurons

Neurotoxicity in the Post-HAART Era: Caution for the Antiretroviral Therapeutics