Abstract
Rationale
MDPV (3,4-methylenedioxypyrovalerone) is a synthetic cathinone present in bath salts. It is a powerful psychostimulant and blocker of the dopamine transporter (DAT), like cocaine. It is known that acute exposure to psychostimulants induces rapid changes in DAT function.
Objectives
To investigate the effects of MDPV on DAT function comparing with cocaine.
Methods
Binding of [3H]WIN 35428 was performed on PC 12 cells treated with MDPV and washed. Rat striatal synaptosomes were incubated with MDPV or cocaine (1 μM) for 1 h and [3H]dopamine (DA) uptake was performed. Also, different treatments with MDPV or cocaine were performed in Sprague-Dawley rats to assess locomotor activity and ex vivo [3H]DA uptake.
Results
MDPV increased surface [3H]WIN 35428 binding on PC 12 cells. In vitro incubation of synaptosomes with MDPV produced significant increases in Vmax and KM for [3H]DA uptake. In synaptosomes from MDPV- (1.5 mg/kg, s.c.) and cocaine- (30 mg/kg, i.p.) treated rats, there was a significantly higher and more persistent increase in [3H]DA uptake in the case of MDPV than cocaine. Repeated doses of MDPV developed tolerance to this DAT upregulation and 24 h after the 5-day treatment with MDPV, [3H]DA uptake was reduced. However, a challenge with the same drugs after withdrawal recovered the DAT upregulation by both drugs and showed an increased response to MDPV vs the first dose. At the same time, animals were sensitized to the stereotypies induced by both psychostimulants.
Conclusions
MDPV induces a rapid and reversible functional upregulation of DAT more powerfully and lasting than cocaine.
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References
Aarde SM, Huang PK, Creehan KM, Dickerson TJ, Taffe MA (2013) The novel recreational drug 3,4-methylenedioxypyrovalerone (MDPV) is a potent psychomotor stimulant: self-administration and locomotor activity in rats. Neuropharmacology 71:130–140. https://doi.org/10.1016/j.neuropharm.2013.04.003
Aliane V, Pérez S, Nieoullon A, Deniau JM, Kemel ML (2009) Cocaine-induced stereotypy is linked to an imbalance between the medial prefrontal and sensorimotor circuits of the basal ganglia. Eur J Neurosci 30:1269–1279. https://doi.org/10.1111/j.1460-9568.2009.06907.x
Alvarez J-C, Fabresse N, Larabi IA (2017) Prevalence and surveillance of synthetic cathinones use by hair analysis: an update review. Curr Pharm Des 23:5487–5495. https://doi.org/10.2174/1381612823666170704124156
Bade R, Bijlsma L, Sancho JV et al (2017) Liquid chromatography-tandem mass spectrometry determination of synthetic cathinones and phenethylamines in influent wastewater of eight European cities. Chemosphere 168:1032–1041. https://doi.org/10.1016/j.chemosphere.2016.10.107
Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, Rothman RB, Goldberg SR, Lupica CR, Sitte HH, Brandt SD, Tella SR, Cozzi NV, Schindler CW (2013) Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive ‘Bath Salts’ products. Neuropsychopharmacology 38:552–562. https://doi.org/10.1038/npp.2012.204
Bowman BP, Vaughan SR, Walker QD et al (1999) Effects of sex and gonadectomy on cocaine metabolism in the rat. J Pharmacol Exp Ther 290:1316–1323
Buenrostro-Jáuregui M, Ciudad-Roberts A, Moreno J, Muñoz-Villegas P, López-Arnau R, Pubill D, Escubedo E, Camarasa J (2016) Changes in CREB and deltaFosB are associated with the behavioural sensitization induced by methylenedioxypyrovalerone. J Psychopharmacol 30:707–712. https://doi.org/10.1177/0269881116645300
Cameron K, Kolanos R, Verkariya R, de Felice L, Glennon RA (2013) Mephedrone and methylenedioxypyrovalerone (MDPV), major constituents of “bath salts,” produce opposite effects at the human dopamine transporter. Psychopharmacology 227:493–499. https://doi.org/10.1007/s00213-013-2967-2
Cervinski MA, Foster JD, Vaughan RA (2005) Psychoactive substrates stimulate dopamine transporter phosphorylation and down-regulation by cocaine-sensitive and protein kinase C-dependent mechanisms. J Biol Chem 280:40442–40449. https://doi.org/10.1074/jbc.M501969200
Chipana C, Camarasa J, Pubill D, Escubedo E (2006) Protection against MDMA-induced dopaminergic neurotoxicity in mice by methyllycaconitine: involvement of nicotinic receptors. Neuropharmacology 51:885–895. https://doi.org/10.1016/j.neuropharm.2006.05.032
Chipana C, García-Ratés S, Camarasa J, Pubill D, Escubedo E (2008) Different oxidative profile and nicotinic receptor interaction of amphetamine and 3,4-methylenedioxy-methamphetamine. Neurochem Int 52:401–410. https://doi.org/10.1016/j.neuint.2007.07.016
Colon-Perez LM, Pino JA, Saha K, Pompilus M, Kaplitz S, Choudhury N, Jagnarine DA, Geste JR, Levin BA, Wilks I, Setlow B, Bruijnzeel AW, Khoshbouei H, Torres GE, Febo M (2018) Functional connectivity, behavioral and dopaminergic alterations 24 hours following acute exposure to synthetic bath salt drug methylenedioxypyrovalerone. Neuropharmacology 137:178–193. https://doi.org/10.1016/j.neuropharm.2018.04.031
Creese I, Iversen SD (1974) The role of forebrain dopamine systems in amphetamine induced stereotyped behavior in the rat. Psychopharmacologia 39:345–357
Daws LC, Callaghan PD, Morón JA, Kahlig KM, Shippenberg TS, Javitch JA, Galli A (2002) Cocaine increases dopamine uptake and cell surface expression of dopamine transporters. Biochem Biophys Res Commun 290:1545–1550. https://doi.org/10.1006/bbrc.2002.6384
Duart-Castells L, Buenrostro-Jáuregui M, Muñoz-Villegas P et al (2017) Repeated exposure of adolescent mice to 3,4-methylenedioxypyrovalerone activates transcriptional mechanisms that persist until adulthood and are similar to those activated by cocaine. Poster communication at Neuroscience 2017 Meeting. http://www.abstractsonline.com/pp8/index.html#!/4376/presentation/29714. Accessed Date: October 1 2018.
Escubedo E, Chipana C, Pérez-Sánchez M et al (2005) Methyllycaconitine prevents methamphetamine-induced effects in mouse striatum: involvement of alpha7 nicotinic receptors. J Pharmacol Exp Ther 315:658–667. https://doi.org/10.1124/jpet.105.089748
Farfel GM, Kleven MS, Woolverton WL, Seiden LS, Perry BD (1992) Effects of repeated injections of cocaine on catecholamine receptor binding sites, dopamine transporter binding sites and behavior in rhesus monkey. Brain Res 578:235–243
Fleckenstein AE, Metzger RR, Wilkins DG et al (1997) Rapid and reversible effects of methamphetamine on dopamine transporters. J Pharmacol Exp Ther 282:834–838
Garcia-Ratés S, Camarasa J, Escubedo E, Pubill David (2007) Methamphetamine and 3,4-methylenedioxymethamphetamine interact with central nicotinic receptors and induce their up-regulation. Toxicol Appl Pharmacol 223(3):195–205. https://doi.org/10.1016/j.taap.2007.05.015
Gatch MB, Taylor CM, Forster MJ (2013) Locomotor stimulant and discriminative stimulus effects of “bath salt” cathinones. Behav Pharmacol 24:437–447. https://doi.org/10.1097/FBP.0b013e328364166d
Giambalvo CT (2003) Differential effects of amphetamine transport vs. dopamine reverse transport on particulate PKC activity in striatal synaptoneurosomes. Synapse 49:125–133. https://doi.org/10.1002/syn.10223
Greene LA, Tischler AS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A 73:2424–2428
Gregg RA, Tallarida CS, Reitz AB, Rawls SM (2013) Mephedrone interactions with cocaine: prior exposure to the ‘bath salt’ constituent enhances cocaine-induced locomotor activation in rats. Behav Pharmacol 24:684–688. https://doi.org/10.1097/FBP.0000000000000006
Gregg RA, Hicks C, Nayak SU, Tallarida CS, Nucero P, Smith GR, Reitz AB, Rawls SM (2016) Synthetic cathinone MDPV downregulates glutamate transporter subtype I (GLT-1) and produces rewarding and locomotor-activating effects that are reduced by a GLT-1 activator. Neuropharmacology 108:111–119. https://doi.org/10.1016/j.neuropharm.2016.04.014
Haberland N, Hetey L (1987) Studies in postmortem dopamine uptake. II Alterations of the synaptosomal catecholamine uptake in postmortem brain regions in schizophrenia. J Neural Transm 68:303–313
Hansen JP, Riddle EL, Sandoval V et al (2002) Methylenedioxymethamphetamine decreases plasmalemmal and vesicular dopamine transport: mechanisms and implications for neurotoxicity. J Pharmacol Exp Ther 300:1093–1100
Haughey HM, Brown JM, Wilkins DG, Hanson GR, Fleckenstein AE (2000) Differential effects of methamphetamine on Na(+)/Cl(−)-dependent transporters. Brain Res 863:59–65
Izenwasser S, Cox BM (1990) Daily cocaine treatment produces a persistent reduction of [3H]dopamine uptake in vitro in rat nucleus accumbens but not in striatum. Brain Res 531:338–341
Johnson PS, Johnson MW (2014) Investigation “bath salts” use patterns within an online sample of users in the United States. J Psychoactive Drugs 46:369–378. https://doi.org/10.1080/02791072.2014.962717
Johnson LA, Furman CA, Zhang M et al (2005) Rapid delivery of the dopamine transporter to the plasmalemmal membrane upon amphetamine stimulation. Neuropharmacology 49:750–758. https://doi.org/10.1016/j.neuropharm.2005.08.018
Kashyap MP, Singh AK, Kumar V, Tripathi VK, Srivastava RK, Agrawal M, Khanna VK, Yadav S, Jain SK, Pant AB (2011) Monocrotophos induced apoptosis in PC12 cells: role of xenobiotic metabolizing cytochrome P450s. PLoS One 6:e17757. https://doi.org/10.1371/journal.pone.0017757
Kesha K, Boggs CL, Ripple MG, Allan CH, Levine B, Jufer-Phipps R, Doyon S, Chi PL, Fowler DR (2013) Methylenedioxypyrovalerone (“bath salts”), related death: case report and review of the literature. J Forensic Sci 58:1654–1659. https://doi.org/10.1111/1556-4029.12202
Kittner B, Bräutigam M, Herken H (1987) PC12 cells: a model system for studying drug effects on dopamine synthesis and release. Arch Int Pharmacodyn Ther 286:181–194
Kolanos R, Solis E, Sakloth F et al (2013) “Deconstruction” of the abused synthetic cathinone methylenedioxypyrovalerone (MDPV) and an examination of effects at the human dopamine transporter. ACS Chem Neurosci 4:1524–1529. https://doi.org/10.1021/cn4001236
Letchworth SR, Daunais JB, Hedgecock AA, Porrino LJ (1997) Effects of chronic cocaine administration on dopamine transporter mRNA and protein in the rat. Brain Res 750:214–222
Little KY, Zhang L, Desmond T et al (1999) Striatal dopaminergic abnormalities in human cocaine users. Am J Psychiatry 156:238–245. https://doi.org/10.1176/ajp.156.2.238
Little KY, Elmer LW, Zhong H et al (2002) Cocaine induction of dopamine transporter trafficking to the plasma membrane. Mol Pharmacol 61:436–445
Loder MK, Melikian HE (2003) The dopamine transporter constitutively internalizes and recycles in a protein kinase C-regulated manner in stably transfected PC12 cell lines. J Biol Chem 278:22168–22174. https://doi.org/10.1074/jbc.M301845200
Lohr KM, Masoud ST, Salahpour A, Miller GW (2017) Membrane transporters as mediators of synaptic dopamine dynamics: implications for disease. Eur J Neurosci 45:20–33. https://doi.org/10.1111/ejn.13357
López-Arnau R, Luján MA, Duart-Castells L, Pubill D, Camarasa J, Valverde O, Escubedo E (2017) Exposure of adolescent mice to 3,4-methylenedioxypyrovalerone increases the psychostimulant, rewarding and reinforcing effects of cocaine in adulthood. Br J Pharmacol 174:1161–1173. https://doi.org/10.1111/bph.13771
Mash DC, Pablo J, Ouyang Q, Hearn WL, Izenwasser S (2002) Dopamine transport function is elevated in cocaine users. J Neurochem 81:292–300
NIDA (2018) Synthetic Cathinones ("Bath Salts"). https://www.drugabuse.gov/publications/drugfacts/synthetic-cathinones-bath-salts. Accessed October 1 2018
Novellas J, López-Arnau R, Carbó ML et al (2015) Concentrations of MDPV in rat striatum correlate with the psychostimulant effect. J Psychopharmacol 29:1209–1918. https://doi.org/10.1177/0269881115598415
Peraile I, Torres E, Mayado A, Izco M, Lopez-Jimenez A, Lopez-Moreno JA, Colado MI, O'Shea E (2010) Dopamine transporter down-regulation following repeated cocaine: implications for 3,4-methylenedioxymethamphetamine-induced acute effects and long-term neurotoxicity in mice. Br J Pharmacol 159:201–211. https://doi.org/10.1111/j.1476-5381.2009.00522.x
Pierce RC, Kalivas PW (1997) A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants. Brain Res Brain Res Rev 25:192–216
Pritchard LM, Hensleigh E, Lynch S (2012) Altered locomotor and stereotyped responses to acute methamphetamine in adolescent, maternally separated rats. Psychopharmacology 223:27–35. https://doi.org/10.1007/s00213-012-2679-z
Pubill D, Chipana C, Camins A, Pallàs M, Camarasa J, Escubedo E (2005) Free radical production induced by methamphetamine in rat striatal synaptosomes. Toxicol Appl Pharmacol 204:57–68. https://doi.org/10.1016/j.taap.2004.08.008
Ramamoorthy S, Shippenberg TS, Jayanthi LD (2011) Regulation of monoamine transporters: role of transporter phosphorylation. Pharmacol Ther 129:220–238. https://doi.org/10.1016/j.pharmthera.2010.09.009
Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661. https://doi.org/10.1096/fj.07-9574LSF
Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ (1987) Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 237:1219–1223
Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18:247–291
Samuvel DJ, Jayanthi LD, Manohar S, Kaliyaperumal K, See RE, Ramamoorthy S (2008) Dysregulation of dopamine transporter trafficking and function after abstinence from cocaine self-administration in rats: evidence for differential regulation in caudate putamen and nucleus accumbens. J Pharmacol Exp Ther 325:293–301. https://doi.org/10.1124/jpet.107.130534
Sandoval V, Riddle EL, Ugarte YV, Hanson GR, Fleckenstein AE (2001) Methamphetamine-induced rapid and reversible changes in dopamine transporter function: an in vitro model. J Neurosci 21:1413–1419
Saunders C, Ferrer JV, Shi L, Chen J, Merrill G, Lamb ME, Leeb-Lundberg LMF, Carvelli L, Javitch JA, Galli A (2000) Amphetamine-induced loss of human dopamine transporter activity: an internalization-dependent and cocaine-sensitive mechanism. Proc Natl Acad Sci U S A 97:6850–6855. https://doi.org/10.1073/pnas.110035297
Schmitt KC, Reith MEA (2010) Regulation of the dopamine transporter: aspects relevant to psychostimulant drugs of abuse. Ann N Y Acad Sci 1187:316–340. https://doi.org/10.1111/j.1749-6632.2009.05148.x
Schmoll S, Romanek K, Stich R, Bekka E, Stenzel J, Geith S, Eyer F, Rabe C (2017) An internet-based survey of 96 German-speaking users of “bath salts”: frequent complications, risky sexual behavior, violence, and delinquency. Clin Toxicol 56:219–222. https://doi.org/10.1080/15563650.2017.1353094
Shekar A, Aguilar JI, Galli G, Cozzi NV, Brandt SD, Ruoho AE, Baumann MH, Matthies HJG, Galli A (2017) Atypical dopamine efflux caused by 3,4-methylenedioxypyrovalerone (MDPV) via the human dopamine transporter. J Chem Neuroanat 83–84:69–74. https://doi.org/10.1016/j.jchemneu.2017.01.004
Simmler L, Buser T, Donzelli M, Schramm Y, Dieu LH, Huwyler J, Chaboz S, Hoener MC, Liechti ME (2013) Pharmacological characterization of designer cathinones in vitro. Br J Pharmacol 168:458–470. https://doi.org/10.1111/j.1476-5381.2012.02145.x
Souza MF, Couto-Pereira NS, Freese L, Costa PA, Caletti G, Bisognin KM, Nin MS, Gomez R, Barros HMT (2014) Behavioral effects of endogenous or exogenous estradiol and progesterone on cocaine sensitization in female rats. Brazilian J Med Biol Res = Rev Bras Pesqui medicas e Biol 47:505–514
Staley JK, Hearn WL, Ruttenber AJ et al (1994) High affinity cocaine recognition sites on the dopamine transporter are elevated in fatal cocaine overdose victims. J Pharmacol Exp Ther 271:1678–1685
Sulzer D, Galli A (2003) Dopamine transport currents are promoted from curiosity to physiology. Trends Neurosci 26:173–176. https://doi.org/10.1016/S0166-2236(03)00063-8
Torres GE, Gainetdinov RR, Caron MG (2003) Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci 4:13–25. https://doi.org/10.1038/nrn1008
Tzschentke TM, Schmidt WJ (2000) Differential effects of discrete subarea-specific lesions of the rat medial prefrontal cortex on amphetamine- and cocaine-induced behavioural sensitization. Cereb Cortex 10:488–498
Watterson LR, Kufahl PR, Taylor SB, Nemirovsky NE, Olive MF (2016) Sensitization to the motor stimulant effects of 3,4-methylenedioxypyrovalerone (MDPV) and cross-sensitization to methamphetamine in rats. J Drug Alcohol Res 235967:1–10. https://doi.org/10.4303/jdar/235967
Wilson JM, Kish SJ (1996) The vesicular monoamine transporter, in contrast to the dopamine transporter, is not altered by chronic cocaine self-administration in the rat. J Neurosci 16:3507–3510
Wright TH, Cline-Parhamovich K, Lajoie D, Parsons L, Dunn M, Ferslew KE (2013) Deaths involving methylenedioxypyrovalerone (MDPV) in upper East Tennessee. J Forensic Sci 58:1558–1562. https://doi.org/10.1111/1556-4029.12260
Zahniser NR, Sorkin A (2009) Trafficking of dopamine transporters in psychostimulant actions. Semin Cell Dev Biol 20:411–417. https://doi.org/10.1016/j.semcdb.2009.01.004
Zuba D, Byrska B (2013) Prevalence and co-existence of active components of ‘legal highs. Drug Test Anal 5:420–429. https://doi.org/10.1002/dta.1365
Acknowledgments
We are grateful to Dr. Anthony L. Riley for helpful critical reading of the manuscript. We also acknowledge Nacho Fargas for eventual technical support.
Funding
This study was supported by grants from Ministerio de Economia y Competitividad (grant SAF2016-75347R) and Plan Nacional sobre Drogas #2014I020, #2016I004). LDC received FPU grants from the Ministerio de Economía y Competitividad (15/02492). JC, LDC, EE, RLA, and DP belong to the quality mentioned group 2017SGR979 by Generalitat de Catalunya. RLA position was funded by an institutional program of the Universitat de Barcelona in collaboration with Obra Social de la Fundació Bancària La Caixa.
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The experimental protocols concerning the use of animals in this work were approved by the Animal Ethics Committee of the University of Barcelona under supervision of the Autonomous Government of Catalonia, following the guidelines of the European Communities Council (86/609/EEC).
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Lopez-Arnau, R., Duart-Castells, L., Aster, B. et al. Effects of MDPV on dopamine transporter regulation in male rats. Comparison with cocaine. Psychopharmacology 236, 925–938 (2019). https://doi.org/10.1007/s00213-018-5052-z
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DOI: https://doi.org/10.1007/s00213-018-5052-z