Rapid regulation of the dopamine transporter: role in stimulant addiction?

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Abstract

Dopamine (DA) and the DA transporter (DAT) play important roles in psychomotor stimulant behavioral activation and reward. By understanding how DAT activity is regulated, we will better appreciate its contribution to normal neurotransmission and to brain diseases like drug addiction. DAT is regulated long-term by chronic drug administration. It is also regulated in a rapid, dynamic fashion by many factors—including brief exposure to DAT substrates, e.g. DA and amphetamine, and inhibitors, e.g. cocaine. We found that individual differences in the initial and sensitized locomotor responsiveness of rats to cocaine reflect differences in in vivo DAT function. Our ex vivo studies have further suggested that differences in basal and/or rapid cocaine-induced expression of functional DATs in striatum contribute to the differences in initial responsiveness. Studies in model systems have demonstrated that short-term DAT regulation occurs by altered transporter trafficking, and thereby cell surface expression. For example, a rapid, complex regulation of DAT by DA is suggested. Amphetamine causes DAT internalization into early endosomal compartments whereas cocaine appears to up-regulate surface expression of DAT. Future studies are needed to confirm these observations in neurons, as well as to elucidate the mechanisms of rapid DAT endocytic trafficking at neuronal synapses.

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).

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