ReviewDifferential effects of stimulants on monoaminergic transporters: Pharmacological consequences and implications for neurotoxicity
Section snippets
Psychostimulants differentially affect dopamine transporters
It has been established that the reinforcing and behavioral effects of psychostimulants are caused, at least in part, by the ability of these agents to increase extraneuronal dopamine concentrations. Some, such as cocaine, cause this increase by preventing the reuptake of newly released dopamine into neurons via the dopamine transporter Heikkila et al., 1975, Nicolaysen and Justice, 1988. Other stimulants, such as amphetamine, purportedly increase dopamine release through a reversal of this
Psychostimulants differentially alter VMAT-2 function
The dopamine transporter-associated ATR may be only one of multiple factors contributing to an increase in intraneuronal dopamine concentrations and eventually neurotoxicity. For instance, it was reported recently that multiple administrations of methamphetamine rapidly (within 1 h) decrease rat striatal VMAT-2 function (Fig. 3; Brown et al., 2000a). This phenomenon may diminish vesicular dopamine storage thereby promoting the accumulation of cytoplasmic dopamine. A similar finding was reported
Psychostimulants differentially affect 5-HT transporters
Like dopamine transporters, 5-HT transporters are also rapidly and reversibly affected by treatment with some psychostimulants. Hence, the ATR associated with 5-HT was assessed. Similar to effects on dopamine transporters, a single injection of methamphetamine, methcathinone or MDMA rapidly (within 1 h) decreases striatal 5-HT transporter function by as much as 20%, as measured in synaptosomes prepared from drug-treated rats. Also, like effects on dopamine transporters, 5-HT transporter
Methamphetamine and the norepinephrine transporter
Like dopamine and 5-HT transporters, the norepinephrine transporter is a member of the Na+–Cl− dependent transporter family and as such shares many structural similarities with these carrier proteins. For instance, molecular biology techniques have revealed that like the dopamine and 5-HT transporters, the norepinephrine transporter contains two conserved cysteine residues located in its large, extracellular loop (Pacholczyk et al., 1991), which in the dopamine transporter is critical for
Summary
Based on the discussion above, psychostimulants differentially alter aminergic transporter function. There are also strong indications that components of the acute effects of these agents on plasmalemmal transporters may contribute to, or at least be predictive of, their long-term neurochemical consequences. For instance, stimulants that cause a rapid dopamine- or 5-HT-associated ATR generally cause long-term dopamine and 5-HT neuronal damage. Stimulants that do not cause these changes do not
Acknowledgements
This research was supported by PHS grants DA 00869, DA 04222, DA 11389 and DA 00378.
References (103)
- et al.
Regulated phosphorylation and trafficking of antidepressant-sensitive serotonin transporter proteins
Biol. Psychiatry
(1998) - et al.
Influence of methamphetamine and neuroleptic drugs on tyrosine hydroxylase activity
Eur. J. Pharmacol.
(1974) - et al.
Enhancement of cocaine-induced hyperthermia fails to elicit neurotoxicity
Neurotoxicol. Teratol.
(1998) - et al.
Dopamine transporter antagonists block phorbol ester-induced dopamine release and dopamine transporter phosphorylation in striatal synaptosomes
Eur. J. Pharmacol.
(2000) - et al.
Methamphetamine-induced neuronal damage: a possible role for free radicals
Neuropharmacology
(1989) - et al.
Striatal subregions are differentially vulnerable to the neurotoxic effects of methamphetamine
Brain Res.
(1992) - et al.
Differential effects of psychostimulants and related agents on dopaminergic and serotonergic transporter function
Eur. J. Pharmacol.
(1999) - et al.
Oxygen radicals diminish dopamine transporter function in rat striatum
Eur. J. Pharmacol.
(1997) Protein kinase C and dopamine transport — 1. Effects of amphetamine in vivo
Neuropharmacology
(1992)- et al.
Oxygen radicals differentially affect Na+/Cl−-dependent transporters
Eur. J. Pharmacol.
(1999)
Studies on the distinction between uptake inhibition and release of [3H]dopamine in rat brain tissue slices
Biochem. Pharmacol.
Methamphetamine-induced serotonin neurotoxicity is mediated by superoxide radicals
Brain Res.
Methamphetamine-stimulated striatal dopamine release declines rapidly over time following microdialysis probe insertion
Brain Res.
The long-term effects of multiple doses of methamphetamine on neostriatal tryptophan hydroxylase, tryosine hydroxylase, choline acetyltransferase and glutamate decarboxylase activities
Life Sci.
Phorbol esters alter functions of the expressed dopamine transporter
Eur. J. Pharmacol.
Lack of long-term monoamine depletions following repeated or continuous exposure to cocaine
Brain Res. Bull.
Methamphetamine treatment rapidly inhibits serotonin, but not glutamate, transporters in rat brain
Brain Res.
Nature of methamphetamine-induced rapid and reversible changes in dopamine transporters
Eur. J. Pharmacol.
Effects of high-dose methamphetamine administration on serotonin uptake sites in rat brain measured using [3H]cyanoimipramine autoradiography
Brain Res.
Comparison of the release of [3H]dopamine from isolated corpus striatum by amphetamine, fenfluramine and unlabelled dopamine
Biochem. Pharmacol.
A cDNA that suppresses MPP+ toxicity encodes a vesicular amine transporter
Cell
Dopamine uptake inhibitors block long-term neurotoxic effects of methamphetamine upon dopaminergic neurons
Brain Res.
Methylenedioxymethamphetamine-induced acute changes in dopamine transporter function
Eur. J. Pharmacol.
Dopamine transporters and neuronal injury
TIPS
Short-term and long-term effects of methamphetamine on biogenic amine metabolism in extra-striatal dopaminergic nuclei
Neuropharmacology
Methamphetamine neurotoxicity and striatal glutamate release: comparison to 3,4-methylenedioxymethamphetamine
Brain Res.
Effects of cocaine on release and dopamine uptake of dopamine in vivo: differentiation by mathematical modeling
Pharmacol. Biochem. Behav.
Multiple methamphetamine injections induce marked increases in extracellular striatal dopamine which correlate with subsequent neurotoxicity
Brain Res.
The acute effects of methamphetamine, amphetamine, and p-chloroamphetamine on the cortical serotonergic system of the rat brain: evidence for differences in the effects of methamphetamine and amphetamine
Eur. J. Pharmacol.
Nitric oxide inhibits [3H]dopamine uptake
Brain Res.
Long-term effects of repeated methylamphetamine administration on monoamine neurons in the rhesus monkey brain
Brain Res.
Fluoxetine increases long-lasting neostriatal dopamine depletion after administration of d-methamphetamine and d-amphetamine
Neuropharmacology
Dopamine nerve terminal degeneration produced by high doses of methylamphetamine in the rat brain
Brain Res.
Further evidence that amphetamines produce long-lasting dopamine neurochemical deficits by destroying dopamine nerve terminals
Brain Res.
Long-term methamphetamine induced changes in brain catecholamines in tolerant rhesus monkeys
Drug Alcohol Depend.
The neurotoxin 1-methyl-4-phenylpyridinium is sequestered within neurons that contain the vesicular monoamine transporter
Neuroscience
The effects of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on monoaminergic systems in the rat brain
Eur J. Pharmacol.
Inhibition of monoamine oxidase by d-methamphetamine
Biochem. Pharmacol.
Protein kinase C-mediated phosphorylation and functional regulation in striatal synaptosomes
Biol. Chem.
Long-lasting depletions of striatal dopamine and loss of dopamine uptake sites following repeated administration of methamphetamine
Brain Res.
Long-term effects of chronic methamphetamine administration in rhesus monkeys
Brain Res.
Lack of neurochemical evidence for neurotoxic effects of repeated cocaine administration in rats on brain monoamine neurons
Drug Alcohol Depend.
Methylphenidate and brain dopamine neurotoxicity
Brain Res.
Methylphenidate and pemoline do not cause depletion of rat brain monoamine markers similar to that observed with methamphetamine
Toxicol. Appl. Pharmacol.
Methamphetamine-induced hyperthermia and dopaminergic neurotoxicity in mice: Pharmacological profile of protective and nonprotective agents
J. Pharmacol. Exp. Ther.
Effects of high-dose fenfluramine treatment on monoamine uptake sites in rat brain: assessment using quantitative autoradiography
Synapse
Immunocytochemical evidence for methamphetamine-induced serotonergic axon loss in the rat brain
Synapse
4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites
J. Pharmacol. Exp. Ther.
Lack of effect of high-dose cocaine on monoamine uptake sites in rat brain measured by quantitative autoradiography
Psychopharmacology (Berlin)
Modification of dopamine transporter function: effect of reactive oxygen species and dopamine
J. Neurochem.
Cited by (190)
Naltrexone-bupropion combinations do not affect cocaine self-administration in humans
2023, Pharmacology Biochemistry and BehaviorHuman behavioral pharmacology of stimulant drugs: An update and narrative review
2022, Advances in PharmacologyMolecular and clinical aspects of potential neurotoxicity induced by new psychoactive stimulants and psychedelics
2021, Experimental NeurologyCitation Excerpt :In addition, the following key words were searched within the journal Forensic Toxicology (Springer) as it was not indexed in PubMed at the time of the study: “NPS + toxicity” (39) “designer drug + toxicity” (55); “amphetamine + toxicity” (55); “cathinone + toxicity” (34); “benzofuran” (7); “indole + NPS”; “indole + designer drug” (39); “aminoindane” (2); “piperazine” (18); “phenidate” (0); “aminorex” (2); “phenmetrazine” (0); “thiophene” (8); “phenethylamine” (51); “tryptamine” (16); “lysergamide” (0). Stimulant NPS modulate monoaminergic neurotransmission either as monoamine transporter inhibitors or as transporter substrates that mediate non-exocytotic substrate efflux (Fleckenstein et al., 2000; Rothman and Baumann, 2003; Sitte and Freissmuth, 2015). In addition, various stimulant NPS interact with monoaminergic receptors, including adrenergic, dopaminergic, and serotonergic receptors, and with trace amine-associated receptor 1 (TAAR1) (Luethi and Liechti, 2020; Simmler et al., 2016).
Topiramate-phentermine combinations reduce cocaine self-administration in humans
2021, Drug and Alcohol Dependence