Rapid regulation of the dopamine transporter: role in stimulant addiction?
Section snippets
Introduction: focus on dopamine and the dopamine transporter
Dopamine (DA) plays an important role in brain reward, both to natural reinforcers and addictive drugs (Wise and Bozarth, 1987, Carboni et al., 1989, Koob, 1992, Kelley and Berridge, 2002, Wise, 2002, Bonci et al., 2003). In fact, most addictive drugs increase extracellular concentrations of DA in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the “brain reward circuit”. A number of lines of early evidence
Long-term regulation of DAT and cocaine-induced behavioral sensitization
In the past, neurotransmitter transporters were considered to be relatively stable constituents of the plasma membrane—essentially they were thought to function like ever-present synaptic vacuum cleaners that were either “on” or “off”. However, within the last 10–15 years, it has become apparent that this picture is incorrect. Many labs, including our own, have shown that the activity of DAT is regulated not only long-term by drug administration, but also short-term in a rapid, dynamic fashion
Differences in DAT and individual responsiveness to cocaine
Differences in initial responsiveness of individuals to drugs of abuse reflect both genetic and environmental influences and are certainly one factor that determines whether or not an individual will become addicted to that drug (e.g. cocaine; Haertzen et al., 1983, Davidson et al., 1993). Thus, we next investigated what might differ about cocaine and its actions in LCRs versus HCRs. We first showed that brain levels of cocaine and the affinity of DAT for cocaine in NAc are similar in LCRs and
Short-term, rapid regulation of DAT
As mentioned above, cocaine exposure can rapidly up-regulate surface DAT expression. In fact, in the past few years it has been shown that DAT uptake activity can be regulated within minutes by changes in membrane potential or exposure to DAT substrates and inhibitors, ligands interacting with presynaptic receptors, signaling molecules that activate/inhibit kinases and phosphatases, and other diffusible second messengers (Zahniser and Doolen, 2001, Gulley and Zahniser, 2003, Kahlig and Galli,
DAT trafficking
Effective and specific targeting of DAT to the synapses of dopaminergic neurons is required for the function of DAT in terminating DA signaling. This targeting involves transport of newly synthesized DAT from the endoplasmic reticulum (ER) through the Golgi complex, where DAT acquires N-glycosylation at the extracellular loops, and to the plasma membrane (Fig. 2). Electron microscopic studies demonstrated that DAT is localized in the plasma membrane of mesocorticolimbic DA neurons mostly in
Summary and future directions
During the past few years, it has become clear that not only is cell surface expression of DAT regulated, but also that it can be regulated rapidly. The dynamic regulation mediated by DA could potentially be complex because of its opposing regulatory effects as a DAT substrate and D2 receptor agonist. It is also provocative that brief exposure to stimulants can result either in transient down-regulation (amphetamines) or up-regulation (cocaine) of DAT expression. Our work suggests that
Acknowledgements
We thank the members of our labs for their many valuable contributions to this work and NIDA for generous support (DA R37 DA04216, R01 DA14204 and K05 DA15050).
References (92)
- et al.
Regulation of the norepinephrine transporter by chronic administration of antidepressants
Biol. Psychiatry
(2004) - et al.
The dopamine-containing neuron: maestro or simple musician in the orchestra of addiction?
Trends Pharmacol. Sci
(2003) - et al.
Amphetamine, cocaine, phencyclidine and nomifensine increase extracellular dopamine concentrations preferentially in the nucleus accumbens of freely moving rats
Neuroscience
(1989) - et al.
Regulated trafficking of the human dopamine transporter—Clathrin-mediated internalization and lysosomal degradation in response to phorbol esters
J. Biol. Chem
(1999) - et al.
Variability in subjective responses to cocaine: initial experiences of college students
Addictive Behav
(1993) - et al.
Cocaine increases dopamine uptake and cell surface expression of dopamine transporters
Biochem. Biophys. Res. Commun
(2002) - et al.
Cocaine reward and MPTP toxicity: alteration by regional variant dopamine transporter overexpression
Mol. Brain Res
(1999) - et al.
Conventional protein kinase C isoforms regulate human dopamine transporter activity in Xenopus oocytes
FEBS Lett
(2002) - et al.
Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat
Brain Res
(2003) - et al.
Differential effects of psychostimulants and related agents on dopaminergic and serotonergic transporter function
Eur. J. Pharmacol
(1999)
Dopamine transporters are phosphorylated on N-terminal serines in rat striatum
J. Biol. Chem
Functional hyperdopaminergia in dopamine transporter knock-out mice
Biol. Psychiatry
It could be habit forming: drugs of abuse and striatal synaptic plasticity
Trends Neurosci
The effect of phosphorylation on amphetamine-mediated outward transport
Eur. J. Pharmacol
N-terminal truncation of the dopamine transporter abolishes phorbol ester- and substance P-stimulated phosphorylation without impairing transporter internalization
J. Biol. Chem
Rapid regulation of dopamine transporter function by blockers, substrates and presynaptic receptor ligands
Eur. J. Pharmacol
Reinforcements from the first drug experience can predict later drug habits and/or addiction: results with coffee, cigarettes, alcohol, barbiturates, minor and major tranquilizers, stimulants, marijuana, hallucinogens, heroin, opiates and cocaine
Drug Alcohol Depen
The human dopamine transporter forms a tetramer in the plasma membrane—cross-linking of a cysteine in the fourth transmembrane segment is sensitive to cocaine analogs
J. Biol. Chem
Dopamine transporter expression distinguishes dopaminergic neurons from other catecholaminergic neurons in the developing zebrafish embryo
Mech. Develop
Analysis of clathrin-mediated endocytosis of epidermal growth factor receptor by RNA interference
J. Biol. Chem
Regulation of dopamine transporter function and plasma membrane expression by dopamine, amphetamine, and cocaine
Eur. J. Pharmacol
Drugs of abuse: anatomy, pharmacology and function of reward pathways
Trends Pharmacol. Sci
Neurochemical changes in cocaine withdrawal
Trends Pharmacol. Sci
The dopamine transporter constitutively internalizes and recycles in a protein kinase C-regulated manner in stably transfected PC12 cell lines
J. Biol. Chem
Serotonin transporters upregulate with chronic cocaine use
J. Chem. Neuroanat
3, 4-methylenedioxymethamphetamine-induced acute changes in dopamine transporter function
Eur. J. Pharmacol
Multiple molecular determinants in the carboxyl-terminus regulate dopamine transporter export from endoplasmic reticulum
J. Biol. Chem
Dynamic regulation of the dopamine transporter
Eur. J. Pharmacol
Stimulant and reinforcing effects of cocaine in monoamine transporter knockout mice
Eur. J. Pharmacol
Drugs, flies, and videotape: the effects of ethanol and cocaine on Drosophila locomotion
Curr. Opin. Neurobiol
Decreased plasma membrane expression of striatal dopamine transporter in aging
Neurobiol. Aging
Oligomerization of dopamine transporters visualized in living cells by fluorescence resonance energy transfer microscopy
J. Biol. Chem
Functional interaction between monoamine plasma membrane transporters and the synaptic PDZ domain-containing protein PICK-1
Neuron
Oligomerization and trafficking of the human dopamine transporter—mutational analysis identifies critical domains important for the functional expression of the transporter
J. Biol. Chem
Drug-activation of brain reward pathways
Drug Alcohol Depend
Brain reward circuitry: insights from unsensed incentives
Neuron
Chronic and acute regulation of Na+/Cl−-dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors and signaling systems
Pharmacol. Ther
Requirement of circadian genes for cocaine sensitization in Drosophila
Science
Trafficking-dependent and -independent pathways of neurotransmitter transporter regulation differentially involving p38 mitogen-activated protein kinase revealed in studies of insulin modulation of norepinephrine transport in SK-N-SH cells
J. Pharmacol. Exp. Ther
Neurotransmitter transporters: regulators of function and functional regulation
J. Membrane Biol
Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level
J. Neurosci
Reward without dopamine
J. Neurosci
Cocaine and amphetamine increase extracellular dopamine in the nucleus accumbens of mice lacking the dopamine transporter gene
J. Neurosci
PI 3-kinase regulation of dopamine uptake
J. Neurochem
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
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2019, NeuropharmacologyCitation Excerpt :In other words, drugs of abuse seem to have in common that they alter VTA DA firing activity by synaptic plastic adaptations (Luscher and Malenka, 2011). It is also worth noting that alterations in both DAT and DA D2 autoreceptor function are seen upon repeated drug exposure (Zahniser and Sorkin, 2004; Ford, 2014). Repeated AMPH administration was e.g. shown to enhance the activity of the regulator of G-protein signaling (RGS) 2 and thereby disrupt coupling between midbrain DA autoreceptors and Gαi.
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