Human Dopamine Transporter Function Following Exposure to Heavy Metals and Psychostimulants
DOI:
https://doi.org/10.17140/TFMOJ-3-124Keywords:
Mercury, Lead, Cocaine, Methamphetamine, Dopamine uptakeAbstract
Background
Environmental exposure to heavy metals plus the use of psychostimulants may pose a unique threat to the neurological health of the user at the level of dopamine transporter (DAT) function.
Objectives
These studies examined the effects of low-concentration heavy metal and psychostimulant (co)exposure on human DAT density and function.
Materials and Methods
Neuro2A neuroblastoma cells (N2A) were exposed to PbCl2 (Pb), HgCl2 (Hg), cocaine (COC), and methamphetamine (MA) to assess alterations in cell viability as well as human dopamine transporter (hDAT) density and function. Assays included Lactate Dehydrogenase activity (cell viability), [3H] GBR12935 binding (hDAT density), and [3H] dopamine (DA) uptake (hDAT functionality). The threshold for changes in cell viability of a metal or stimulant is the concentration used in mixture exposure studies (10 μM for Hg and Pb; 100 nM for COC and MA) with an optimum exposure time of 72 h.
Results
Both Hg and Pb reduced cell viability related to exposure time and concentration. N2A cells demonstrated greater resistance to COC- and MA-induced cytotoxicity. The density of hDAT increased (115-175%) following exposure to Hg, Pb, COC, or MA compared to vehicle values. After exposure to metal-psychostimulant mixtures, hDAT density increased 161-288% compared to control values. We observed the largest increase in [3H] DA uptake in the MA group (35-81%), whereas COC groups inhibited uptake (17-20%). Collectively, exposures to each compound (alone or mixture) increased hDAT density. Our observations suggest that increased protein present did not translate to increased functionality, since changes in [3H] DA uptake did not parallel density changes.
Conclusion
Although more hDAT protein is at the cell surface, altered function results in an inability to clear [3H] DA from the extracellular space. Thus, exposure to low-levels of heavy metals may increase the risk for altered DA neurotransmission/turnover following psychostimu-lant use, resulting in an exaggerated response or increased risk for toxicity.
References
Dela Peña I, Gevorkiana R, Shi WX. Psychostimulants affect dopamine transmission through both dopamine transporter-de-pendent and independent mechanisms. Eur J Pharmacol. 2015; 764: 562-570. doi: 10.1016/j.ejphar.2015.07.044
Cass WA, Gerhardt GA, Gillespie K, Curella P, Mayfield RD, Zahniser NR. Reduced clearance of exogenous dopamine in rat nucleus accumbens, but not in dorsal striatum, following cocaine challenge in rats withdrawn from repeated cocaine administration. J Neurochem. 1993; 61(1): 273-283. doi: 10.1111/j.1471-4159.1993. tb03565.x
Heal DJ, Gosden J, Smith SL. Dopamine reuptake transporter (DAT) “inverse agonism” - A novel hypothesis to explain the enig-matic pharmacology of cocaine. Neuropharmacology. 2014; 87: 19-40. doi: 10.1016/j.neuropharm.2014.06.012
Curtis JT, Hood AN, Chen Y, Cobb GP, Wallace DR. Chronic metals ingestion by prairie voles produces sex-specific deficits in social behavior: An animal model of autism. Behav Brain Res. 2010; 213(1): 42-49. doi: 10.1016/j.bbr.2010.04.028
Jones DC, Miller GW. The effects of environmental neurotox-icants on the dopaminergic system: A possible role in drug ad-diction. Biochem Pharmacol. 2008; 76(5): 569-581. doi: 10.1016/j. bcp.2008.05.010
Chang J, Kueon C, Kim J. Influence of lead on repetitive behav-ior and dopamine metabolism in a mouse model of iron overload. Toxicol Res. 2014; 30(4): 267-276. doi: 10.5487/TR.2014.30.4.267
Cory-Slechta D. Relationships between lead-induced learning im-pairments and changes in dopaminergic, cholinergic and glutama-tergic neurotransmitter system functions. Annu Rev Pharmacol Toxi-col. 1995; 35: 391-415. doi: 10.1146/annurev.pa.35.040195.002135
Pokora MJ, Richfield EK, Cory-Slechta DA. Preferential vulner-ability of nucleus accumbens dopamine binding sites to low-level lead exposure: Time course of effects and interactions with chronic dopamine agonist treatments. J Neurochem. 1996; 67(4): 1540-1550. doi: 10.1046/j.1471-4159.1996.67041540.x
Noureddine D, Miloud S, Abdelkader A. Effect of lead exposure Original Research | Volume 3 | Number 1| Wallace DR, et al on dopaminergic transmission in the rat brain. Int J Child Neuropsy-chiatry. 2004; 1(1): 97-105. doi: 10.1016/j.tox.2004.10.016
Ranaldi R, Wise RA. Blockade of D1 dopamine receptors in the ventral tegmental area decreases cocaine reward: Possible role for dendritically released dopamine. J Neurosci. 2001; 21(15): 5841- 5846. doi: 10.1523/JNEUROSCI.21-15-05841.2001
Mash DC, Pablo J, Ouyang Q, Hearn WL, Izenwasse S. Dopa-mine transport function is elevated in cocaine users. J Neurochem. 2002; 81(2): 292-300. doi: 10.1046/j.1471-4159.2002.00820.x
Daws LC, Callaghan PD, Morón JA, et al. Cocaine increases dopamine uptake and cell surface expression of dopamine trans-porters. Biochem Biophys Res Commun. 2002; 290(5): 1545-1550. doi: 10.1006/bbrc.2002.6384
Wu Q, Coffey LL, Reith ME. Cations affect [3H]mazindol and [3H]WIN 35,428 binding to the human dopamine transport-er in a similar fashion. J Neurochem. 1997; 69(3): 1106-1118. doi: 10.1046/j.1471-4159.1997.69031106.x
Vidal L, Alfonso M, Faro LF, Campos F, Cervantes R, Durán R. Evaluation of the effects and mechanisms of action of mercu-ric chloride on striatal dopamine release by using in vivo microdi-alysis in freely moving rats. Toxicology. 2007; 236(1-2): 42-49. doi: 10.1016/j.tox.2007.03.023
Fleckenstein AE, Volz TJ, Riddle EL, Gibb JW, Hanson GR. New insights into the mechanism of action of amphetamines. Annu Rev Pharmacol Toxicol. 2007; 47(1): 681-698. doi: 10.1146/an-nurev.pharmtox.47.120505.105140
Mortensen OV, Amara SG. Dynamic regulation of the dopa-mine transporter. Eur J Pharmacol. 2003; 479(1-3): 159-170. doi: 10.1016/j.ejphar.2003.08.066
Faro LRF, Do Nascimento JLM, Alfonso M, Durán R. In vivo effects of inorganic mercury (HgCl ) on striatal dopaminergic sys-tem. Ecotoxicol Environ Saf. 2001; 48(3): 263-267. doi: 10.1006/ eesa.2000.2024
Weinstein M, Bernstein S. Pink ladies: Mercury poisoning in twin girls. Can Med Assoc J. 2003; 168(2): 201.
Ricaurte G, Guillery R, Seiden L, Schuster C, Moore R. Dopa-mine nerve terminal degeneration produced by high doses of me-thylamphetamine in the rat brain. Brain Res. 1982; 235(1): 93-103. doi: 10.1016/0006-8993(82)90198-6
Seiden L, Ricaurte G. Neurotoxicity of methamphetamine and related drugs. In: Meltzer H, ed. Psychopharmacology: The Third Gen-eration of Progress. New York, USA: Raven Press; 1987: 359-366.
Gibb J, Hanson G, Johnson M. Neurochemical mechanisms of toxicity. In: Cho A, Segal D, eds. Amphetamine and Its Analogues: Psychopharmacology, Toxicology and Abuse. San Diego, CA, USA: Aca-demic Press; 1994: 269-295.
Cass WA. Decreases in evoked overflow of dopamine in rat striatum after neurotoxic doses of methamphetamine. J Pharmacol Exp Ther. 1997; 280(1): 105-113.
Bennett BA, Hollingsworth CK, Martin RS, Harp JJ. Meth-amphetamine-induced alterations in dopamine transporter func-tion. Brain Res. 1998; 782(1-2): 219-227. doi: 10.1016/S0006- 8993(97)01281-X
Kokoshka JM, Vaughan RA, Hanson GR, Fleckenstein AE. Nature of methamphetamine-induced rapid and reversible changes in dopamine transporters. Eur J Pharmacol. 1998; 361(2-3): 269-275. doi: 10.1016/S0014-2999(98)00741-9
Kimmel HL, Carroll FI, Kuhar MJ. Dopamine transporter synthesis and degradation rate in rat striatum and nucleus accum-bens using RTI-76. Neuropharmacology. 2000; 39(4): 578-585. doi: 10.1016/S0028-3908(99)00160-4
NIDA. Cocaine. 2016. Web site. https://d14rmgtrwzf5a. cloudfront.net/sites/default/files/drugfacts-cocaine.pdf. Ac-cessed April 19, 2018.
NIDA. Methamphetamine. 2017. Web site. https://d14rmg-trwzf5a.cloudfront.net/sites/default/files/df_methamphet-amine_february2017_1.pdf. Accessed April 19, 2018.
Izenwasser S, Cox B. Daily cocaine treatment produces a per-sistent reduction of [3H]dopamine uptake in vitro in rat nucleus accumbens but not in striatum. Brain Res. 1990; 531(1-2): 338-341. doi: 10.1016/0006-8993(90)90797-F
Verma V. Classic studies on the interaction of cocaine and the dopamine transporter. Clin Psychopharmacol Neurosci. 2015; 13(3): 227-238. doi: 10.9758/cpn.2015.13.3.227
Kalivas PW, Duffy P. Effect of acute and daily cocaine treat-ment on extracellular dopamine in the nucleus accumbens. Synapse. 1990; 5(1): 48-58. doi: 10.1002/syn.890050104
Beuming T, Kniazeff J, Bergmann ML, et al. The binding sites for cocaine and dopamine in the dopamine transporter overlap. Nat Neurosci. 2008; 11(7): 780-789. doi: 10.1038/nn.2146
Zahniser NR, Larson GA, Gerhardt GA. In vivo dopamine clearance rate in rat striatum: Regulation by extracellular dopamine concentration and dopamine transporter inhibitors. J Pharmacol Exp Ther. 1999; 289(1): 266-277. Web site. http://jpet.aspetjour-nals.org/content/289/1/266.long. Accessed April 19, 2018.
Kahlig KM, Galli A. Regulation of dopamine transporter func-tion and plasma membrane expression by dopamine, amphet-amine, and cocaine. Eur J Pharmacol. 2003; 479(1-3): 153-158. doi: 10.1016/j.ejphar.2003.08.065
Zahniser NR, Sorkin A. Rapid regulation of the dopamine transporter: Role in stimulant addiction? Neuropharmacology. 2004; 47(Suppl. 1): 80-91. doi: 10.1016/j.neuropharm.2004.07.010 12 Wallace DR, et al
Fleckenstein AE, Haughey HM, Metzger RR, et al. Differen-tial effects of psychostimulants and related agents on dopaminer-gic and serotonergic transporter function. Eur J Pharmacol. 1999; 382(1): 45-49. doi: 10.1016/S0014-2999(99)00588-9
Saunders C, Ferrer J V., Shi L, et al. Amphetamine-induced loss of human dopamine transporter activity: An internalization-dependent and cocaine-sensitive mechanism. Proc Natl Acad Sci. 2000; 97(12): 6850-6855. doi: 10.1073/pnas.110035297
Aronstam RS, Mohyee EE. Transition and heavy metal in-hibition of ligand binding to muscarinic acetylcholine receptors from rat brain. Toxicol Appl Pharmacol. 1979; 48(3): 489-496. doi: 10.1016/0041-008X(79)90432-0
Von Berg R, Northington F, Shamoo A. Methylmercury inhibi-tion of rat brain muscarinic receptors. Toxicol Appl Pharmacol. 1980; 53(2): 285-292. doi: 10.1016/0041-008X(80)90428-7
Min MO, Singer LT, Kirchner HL, et al. Cognitive development and low-level lead exposure in poly-drug exposed children. Neuro-toxicol Teratol. 2009; 31(4): 225-231. doi: 10.1016/j.ntt.2009.03.002
Lidsky TI, Schneider JS. Lead neurotoxicity in children: Basic mechanisms and clinical correlates. Brain. 2003; 126(1): 5-19. doi: 10.1093/brain/awg014
Yoon JH, Ahn YS. The association between blood lead level and clinical mental disorders in fifty thousand lead-exposed male work-ers. J Affect Disord. 2016; 190: 41-46. doi: 10.1016/j.jad.2015.09.030
Lin C, Liou S, Hsiech C, Ku M, Tsai S. Dose-response relation-ship between cumulative mercury exposure index and specific up-take ratio in the striatum on Tc-99m TRODAT SPECT. Clincial Nucl Med. 2011; 36(8): 689-693. doi: 10.1097/RLU.0b013e3181e9fa93
Faro LRF, do Nascimento JLM, Alfonso M, Durán R. Pro-tection of methylmercury effects on the in vivo dopamine release by NMDA receptor antagonists and nitric oxide synthase inhibi-tors. Neuropharmacology. 2002; 42(5): 612-618. doi: 10.1016/S0028- 3908(02)00009-6
Faro LRF, Do Nascimento JLM, Alfonso M, Durán R. Mech-anism of action of methylmercury on in vivo striatal dopamine release: Possible involvement of dopamine transporter. Neurochem Int. 2002; 40(5): 455-465. doi: 10.1016/S0197-0186(01)00098-5
Faro LRF, Durán R, Do Nascimento JLM, Perez-Vences D, Alfonso M. Effects of successive intrastriatal methylmercury ad-ministrations on dopaminergic system. Ecotoxicol Environ Saf. 2003; 55(2): 173-177. doi: 10.1016/S0147-6513(02)00127-6
Faro LRF, Rodrigues KJA, Santana MB, Vidal L, Alfonso M, Durán R. Comparative effects of organic and inorganic mercury on in vivo dopamine release in freely moving rats. Brazilian J Med Biol Res. 2007; 40: 1361-1365. doi: 10.1590/S0100-879X2006005000157
Schweri M. Mercuric chloride and p-chloromercuriphenylsul-Original Research | Volume 3 | Number 1| fonate exert a biphasic effect on the binding of the stimulant [3H] methylphenidate to the dopamine transporter. Synapse. 1994; 16(3): 188-194. doi: 10.1002/syn.890160304
Li Y, Mayer FP, Hasenhuetl PS, et al. Occupancy of the zinc-binding site by transition metals decreases the substrate affinity of the human dopamine transporter by an allosteric mechanism. J Biol Chem. 2017; 292(10): 4235-4243. doi: 10.1074/jbc.M116.760140
Ritz M, Lamb R, Goldberg S, Kuhar M. Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science. 1987; 237(4819): 1219-1223. doi: 10.1126/science.2820058
Jones SR, Gainetdinov RR, Wightman RM, Caron MG. Mech-anisms of amphetamine action revealed in mice lacking the dopa-mine transporter. J Neurosci. 1998; 18(6): 1979-1986.
Aronstam RS, Abood LG, Hoss W. Influence of sulfhydryl reagents and heavy metals on the functional state of the musca-rinic acetylcholine receptor in rat brain. Mol Pharmacol. 1978; 14: 575-586.
Peterson L Lou, Bartfai T. In vitro and in vivo inhibition of [3H]imipramine binding by cadmium. Eur J Pharmacol. 1983; 90(2- 3): 289-292. doi: 10.1016/0014-2999(83)90252-2
Mizuno S, Ogawa N, Mori A. Differential effects of some tran-sition metal cations on the binding of beta-carboline-3-carboxylate and diazepam. Neurochem Res. 1983; 8(7): 873-880. doi: 10.1007/ BF00964548
Kniazeff J, Loland CJ, Goldberg N, et al. Intramolecular cross-linking in a bacterial homolog of mammalian SLC6 neurotrans-mitter transporters suggests an evolutionary conserved role of transmembrane segments 7 and 8. Neuropharmacology. 2005;49(6): 715-723. doi: 10.1016/j.neuropharm.2005.07.003
Daniels GM, Amara SG. Regulated trafficking of the human Original Research | Volume 3 | Number 1| Wallace DR, et al dopamine transporter. J Biol Chem. 1999; 274(50): 35794-35801.
Struzynska L, Rafalowska U. The effect of lead on dopamine, GABA and histidine spontaneous and KCl-dependent releases from rat brain synaptosomes. Acta Neurobiol Exp (Wars). 1994; 54(3): 201-207.
Zhang L, Elmer LW, Little KY. Expression and regula-tion of the human dopamine transporter in a neuronal cell line. Brain Res Mol Brain Res. 1998; 59(1): 66-73. doi: 10.1016/S0169- 328X(98)00138-7
Little KY, Elmer LW, Zhong H, Scheys JO, Zhang L. Co-caine induction of dopamine transporter trafficking to the plasma membrane. Mol Pharmacol. 2002; 61(2): 436-445. doi: 10.1124/ mol.61.2.436
Sharpe L, Pilotte N, Mitchell W, DeSouza E. Withdrawal of re-peated cocaine decreases autoradlographic [3H]mazindol-labelling of dopamine transporter in rat nucleus accumbens. Eur J Pharmacol. 1991; 203(1): 141-144. doi: 10.1016/0014-2999(91)90804-Y
David DJ, Zahniser NR, Hoffer BJ, Gerhardt GA. In vivo electrochemical studies of dopamine clearance in subregions of rat nucleus accumbens: Differential properties of the core and shell. Exp Neurol. 1998; 153(2): 277-286. doi: 10.1006/exnr.1998.6898
Ho M, Segre M. Individual and combined effects of ethanol and cocaine on the human dopamine transporter in neuronal cell lines. Neurosci Lett. 2001; 299(3): 229-233. doi: 10.1016/S0304- 3940(01)01526-9
Segal D, Kuczenski R. Repeated cocaine administration induc-es behavioral sensitization and corresponding decreased extracellu-lar dopamine responses in caudate and accumbens. Brain Res. 1992; 577(2): 351-355. doi: 10.1016/0006-8993(92)90297-M
Downloads
Published
How to Cite
Issue
Section
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
All content published in Toxicology and Forensic Medicine (TFM) is licensed under the Creative Commons Attribution 4.0 International License (CC BY 4.0). This license allows anyone to copy, distribute, transmit, and adapt the work — including for commercial purposes — provided appropriate credit is given to the original author(s) and source.
