Effects of MDPV on dopamine transporter regulation in male rats. Comparison with cocaine
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.
To investigate the effects of MDPV on DAT function comparing with cocaine.
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.
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.
MDPV induces a rapid and reversible functional upregulation of DAT more powerfully and lasting than cocaine.
KeywordsBath salts Cathinones Cocaine Dopamine transporter Dopamine uptake MDPV Upregulation
We are grateful to Dr. Anthony L. Riley for helpful critical reading of the manuscript. We also acknowledge Nacho Fargas for eventual technical support.
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.
Compliance with ethical standards
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).
Conflict of interest
The authors declare that there is no conflict of interest.
- 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 CrossRefPubMedPubMedCentralGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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.
- 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 CrossRefPubMedPubMedCentralGoogle Scholar
- 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 CrossRefPubMedPubMedCentralGoogle Scholar
- 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 CrossRefPubMedPubMedCentralGoogle Scholar
- 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 CrossRefPubMedPubMedCentralGoogle Scholar
- NIDA (2018) Synthetic Cathinones ("Bath Salts"). https://www.drugabuse.gov/publications/drugfacts/synthetic-cathinones-bath-salts. Accessed October 1 2018
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedPubMedCentralGoogle Scholar
- 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 CrossRefGoogle Scholar
- 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 CrossRefPubMedPubMedCentralGoogle Scholar
- 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 47:505–514CrossRefGoogle Scholar