Improved Understanding of Dopamine Signaling---Implications for Drug Development

A Mechanism for Amphetamine-Induced Dopamine Overload

DOI: 10.1371/journal.pbio.0020087
Published March 16, 2004

Copyright: © 2004 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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The notion of a neurally encoded "reward system" that reinforces pleasure-seeking behaviors first emerged fifty years ago. Psychologists James Olds and Peter Milner discovered this phenomenon when their "lack of aim" landed an electrode outside their target while studying the behavioral responses of rats given electrical stimulation to a particular brain region. It was known that stimulation of certain brain regions would induce an animal to avoid the behavior that produced the stimulus. But in the rat with the "misplaced" electrode, stimulation of this new region caused the rat to repeat the behavior that caused the stimulus. Stimulation of certain brain regions provides a very strong incentive to restimulate, creating a feedback loop that reinforces both the behavior and the neural response to it. When gentle shocks were delivered to the rat hypothalamus, for example, the animals would "self-stimulate" 2,000 times per hour by pushing a lever. The neurotransmitter dopamine, it was later discovered, plays an important role in the brain's reward system -- and in laying the biochemical foundation of drug addiction.

Essential for normal central nervous system function, dopamine signaling mediates physiological functions as diverse as movement and lactation. The dopamine transporter (DAT) is involved in terminating dopamine signaling by removing the dopamine chemical messenger molecules from nerve synapses and returning them into the releasing neurons (a process called reuptake). DAT can also bind amphetamine, cocaine, and other psychostimulants, which inhibit dopamine reuptake, and, in the case of amphetamine, also stimulate the release of dopamine through DAT. It's thought that abnormal concentrations of dopamine in synapses initiate a series of events that cause the behavioral effects of these drugs.

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The researchers found that amphetamine-induced dopamine release was reduced by 80% in cells expressing a mutant dopamine transporter in which the first 22 amino acids of the N-terminal domain had been removed (del-22). Surprisingly, this truncated transporter displayed normal dopamine uptake. In a full-length DAT, mutation of the five N-terminal serine amino acids to alanine amino acids, which prevented phosphorylation, produced an effect similar to removing the 22 amino acids. In contrast, replacing these five serine residues with aspartate residues to mimic phosphorylation led to normal dopamine release as well as normal dopamine uptake.

These findings suggest that phosphorylation of one or more of these serine residues is necessary for amphetamine to flood the synapses with dopamine. While phosphorylation is a normal mechanism for regulating protein activity in a cell -- and DAT is "significantly phosphorylated" under normal conditions -- amphetamine could increase the level of DAT phosphorylation. Elucidating the mechanisms through which phosphorylation of DAT's N-terminus facilitates dopamine overload could lead to the development of drugs that block the "rewarding" effects of amphetamines and other addictive psychostimulants without interfering with normal dopamine clearance.

Analysis:  The text above is a layperson-accessible report distilled from a article published in PLoS Biology, N-Terminal Phosphorylation of the Dopamine Transporter Is Required for Amphetamine-Induced Efflux.  The technical writer points out that the new understanding of the dopamine transporter could lead to development of drugs to treat addiction to psychostimulants.  That is true, but I think they missed two implications that potentially could be much greater.  Schizophrenia and other psychoses have a complex pathophysiology, but excess dopamine signaling is an important part of most, if not all, psychoses.   If this research could lead to development of a new class of antipsychotic medication, that would be a tremendous advance in psychopharmacology.  The number of persons with psychostimulants addiction is small; the number of persons with schizophrenia is large.  Looking at it the other way, if this could lead to new ways to increase dopamine output safely, it could lead to treatments for Parkinson's Disease and other causes of Parkinsonian symptoms.