Effects of MDPV on Dopamine Transporter Regulation in Male Rats. Comparison with Cocaine

Overview

Journal Psychopharmacology (Berl)

Specialty Pharmacology

Date 2018 Oct 5

PMID 30284596

Citations 10

Authors

Raul Lopez-Arnau

Leticia Duart-Castells

Barbara Aster

Jorge Camarasa

Elena Escubedo

David Pubill

Affiliations

Soon will be listed here.

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 [H]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 [H]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 [H]DA uptake.

Results: MDPV increased surface [H]WIN 35428 binding on PC 12 cells. In vitro incubation of synaptosomes with MDPV produced significant increases in V and K for [H]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 [H]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, [H]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.

Citing Articles

Structure-Activity Relationship of Synthetic Cathinones: An Updated Review.

Nadal-Gratacos N, Pazos M, Pubill D, Camarasa J, Escubedo E, Berzosa X ACS Pharmacol Transl Sci. 2024; 7(9):2588-2603.

PMID: 39296271 PMC: 11406692. DOI: 10.1021/acsptsci.4c00299.

Unlocking the Potential of High-Quality Dopamine Transporter Pharmacological Data: Advancing Robust Machine Learning-Based QSAR Modeling.

Lee K, Won S, Oyinloye P, Shi L bioRxiv. 2024; .

PMID: 38558976 PMC: 10979915. DOI: 10.1101/2024.03.06.583803.

Synthetic Cathinones and Neurotoxicity Risks: A Systematic Review.

Daziani G, Lo Faro A, Montana V, Goteri G, Pesaresi M, Bambagiotti G Int J Mol Sci. 2023; 24(7).

PMID: 37047201 PMC: 10093970. DOI: 10.3390/ijms24076230.

Structure-Activity Relationship of -Ethyl-Hexedrone Analogues: Role of the α-Carbon Side-Chain Length in the Mechanism of Action, Cytotoxicity, and Behavioral Effects in Mice.

Nadal-Gratacos N, Rios-Rodriguez E, Pubill D, Batllori X, Camarasa J, Escubedo E ACS Chem Neurosci. 2023; 14(4):787-799.

PMID: 36734852 PMC: 9936538. DOI: 10.1021/acschemneuro.2c00772.

Cannabidiol Modulates the Motivational and Anxiety-Like Effects of 3,4-Methylenedioxypyrovalerone (MDPV) in Mice.

Alegre-Zurano L, Lopez-Arnau R, Lujan M, Camarasa J, Valverde O Int J Mol Sci. 2021; 22(15).

PMID: 34361071 PMC: 8348800. DOI: 10.3390/ijms22158304.

References

Bowman B, Vaughan S, Walker Q, Davis S, Little P, Scheffler N . Effects of sex and gonadectomy on cocaine metabolism in the rat. J Pharmacol Exp Ther. 1999; 290(3):1316-23. View

Greene L, Tischler A . Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A. 1976; 73(7):2424-8. PMC: 430592. DOI: 10.1073/pnas.73.7.2424. View

Haughey H, Brown J, Wilkins D, Hanson G, Fleckenstein A . Differential effects of methamphetamine on Na(+)/Cl(-)-dependent transporters. Brain Res. 2000; 863(1-2):59-65. DOI: 10.1016/s0006-8993(00)02094-1. View

Saunders C, Ferrer J, Shi L, Chen J, Merrill G, Lamb M . Amphetamine-induced loss of human dopamine transporter activity: an internalization-dependent and cocaine-sensitive mechanism. Proc Natl Acad Sci U S A. 2000; 97(12):6850-5. PMC: 18764. DOI: 10.1073/pnas.110035297. View

Tzschentke T, Schmidt W . Differential effects of discrete subarea-specific lesions of the rat medial prefrontal cortex on amphetamine- and cocaine-induced behavioural sensitization. Cereb Cortex. 2000; 10(5):488-98. DOI: 10.1093/cercor/10.5.488. View

Sandoval V, Riddle E, Ugarte Y, Hanson G, Fleckenstein A . Methamphetamine-induced rapid and reversible changes in dopamine transporter function: an in vitro model. J Neurosci. 2001; 21(4):1413-9. PMC: 6762246. View

Little K, Elmer L, Zhong H, Scheys J, Zhang L . Cocaine induction of dopamine transporter trafficking to the plasma membrane. Mol Pharmacol. 2002; 61(2):436-45. DOI: 10.1124/mol.61.2.436. View

Daws L, Callaghan P, Moron J, Kahlig K, Shippenberg T, Javitch J . Cocaine increases dopamine uptake and cell surface expression of dopamine transporters. Biochem Biophys Res Commun. 2002; 290(5):1545-50. DOI: 10.1006/bbrc.2002.6384. View

Hansen J, Riddle E, Sandoval V, Brown J, Gibb J, Hanson G . Methylenedioxymethamphetamine decreases plasmalemmal and vesicular dopamine transport: mechanisms and implications for neurotoxicity. J Pharmacol Exp Ther. 2002; 300(3):1093-100. DOI: 10.1124/jpet.300.3.1093. View

10.

Mash D, Pablo J, Ouyang Q, Hearn W, Izenwasser S . Dopamine transport function is elevated in cocaine users. J Neurochem. 2002; 81(2):292-300. DOI: 10.1046/j.1471-4159.2002.00820.x. View

11.

Torres G, Gainetdinov R, Caron M . Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci. 2003; 4(1):13-25. DOI: 10.1038/nrn1008. View

12.

Loder M, Melikian H . The dopamine transporter constitutively internalizes and recycles in a protein kinase C-regulated manner in stably transfected PC12 cell lines. J Biol Chem. 2003; 278(24):22168-74. PMC: 2597781. DOI: 10.1074/jbc.M301845200. View

13.

Sulzer D, Galli A . Dopamine transport currents are promoted from curiosity to physiology. Trends Neurosci. 2003; 26(4):173-6. DOI: 10.1016/S0166-2236(03)00063-8. View

14.

Giambalvo C . Differential effects of amphetamine transport vs. dopamine reverse transport on particulate PKC activity in striatal synaptoneurosomes. Synapse. 2003; 49(2):125-33. DOI: 10.1002/syn.10223. View

15.

Farfel G, Kleven M, Woolverton W, Seiden L, Perry B . Effects of repeated injections of cocaine on catecholamine receptor binding sites, dopamine transporter binding sites and behavior in rhesus monkey. Brain Res. 1992; 578(1-2):235-43. DOI: 10.1016/0006-8993(92)90252-5. View

16.

Pubill D, Chipana C, Camins A, Pallas M, Camarasa J, Escubedo E . Free radical production induced by methamphetamine in rat striatal synaptosomes. Toxicol Appl Pharmacol. 2005; 204(1):57-68. DOI: 10.1016/j.taap.2004.08.008. View

17.

Escubedo E, Chipana C, Perez-Sanchez M, Camarasa J, Pubill D . Methyllycaconitine prevents methamphetamine-induced effects in mouse striatum: involvement of alpha7 nicotinic receptors. J Pharmacol Exp Ther. 2005; 315(2):658-67. DOI: 10.1124/jpet.105.089748. View

18.

Cervinski M, Foster J, Vaughan R . Psychoactive substrates stimulate dopamine transporter phosphorylation and down-regulation by cocaine-sensitive and protein kinase C-dependent mechanisms. J Biol Chem. 2005; 280(49):40442-9. DOI: 10.1074/jbc.M501969200. View

19.

Johnson L, Furman C, Zhang M, Guptaroy B, Gnegy M . Rapid delivery of the dopamine transporter to the plasmalemmal membrane upon amphetamine stimulation. Neuropharmacology. 2005; 49(6):750-8. DOI: 10.1016/j.neuropharm.2005.08.018. View

20.

Chipana C, Camarasa J, Pubill D, Escubedo E . Protection against MDMA-induced dopaminergic neurotoxicity in mice by methyllycaconitine: involvement of nicotinic receptors. Neuropharmacology. 2006; 51(4):885-95. DOI: 10.1016/j.neuropharm.2006.05.032. View