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Durham, N.C. -- Duke University Medical Center researchers
have discovered a new mechanism by which chronically high
levels of the neurotransmitter dopamine exert their effects on
the brain. Normally associated with triggering feelings of
pleasure, excess concentrations of dopamine underlie
schizophrenia, attention deficit hyperactivity disorder and
other psychiatric conditions. The findings therefore provide
new research avenues to understand and potentially manage such
dopamine-related human disorders, the researchers said.

"We've thought that neurotransmitters relay messages to the
brain in two speeds: fast and slow," said lead author of the
study Jean-Martin Beaulieu, Ph.D. of Duke. "However, our new
findings reveal that brain receptors that respond to dopamine
actually have two slow modes: one that takes place over a
period of minutes and a second -- newly discovered -- that
lasts for hours. In fact, it may be that this effect continues
for as long as dopamine remains in the system."

This sustained action of dopamine may be particularly
important for understanding psychiatric conditions, which are
characterized by persistently high levels of the brain
messenger, Beaulieu said. The researchers report their findings
in the July 29, 2005, issue of Cell.

"This mechanism appears to be more important than those
earlier described for prolonged stimulation by dopamine, as
would be the case in those with psychiatric conditions," said
senior author Marc Caron, Ph.D., of Duke. "The new pathway can
now be evaluated for potential new inhibitors that might be
better at controlling particular psychotic behaviors." Caron is
a professor of cell biology at Duke and faculty member at the
Duke Institute for Genome
Sciences & Policy.

Dopamine's prolonged effects might also apply to
understanding the impact of sustained drug use on the brain,
Caron added. Virtually all addictive drugs, including cocaine
and amphetamines, directly or indirectly raise dopamine levels.
The neurotransmitter therefore plays a major role in
drug-induced highs and in addiction, he explained.

Neurotransmitters such as dopamine are chemical messengers
that one neuron launches at receptors on another to trigger a
nerve impulse in the receiving neuron. Receptors are protein
switches on the surfaces of neurons that recognize
neurotransmitters and translate their signals into a cellular
response. Dopamine exerts its functions in the brain by binding
to two broad classes of receptors -- one class that transmits
signals fast and another that acts through signaling pathways
to relay messages more slowly.

Dopamine receptors exist in two forms, D1 and D2 class
receptors, both belonging to a class of slow-acting receptors
known as G protein-coupled receptors. One method by which
dopamine relays messages to the brain over a period of minutes
has been well worked out. The new study by Caron and his
colleagues reveals a second mechanism whereby chronic dopamine
affects the brain, perhaps indefinitely.

The Duke team's previous work suggested that the regulatory
protein beta-arrestin 2, normally involved in desensitization
of receptor signals, is required for normal dopamine-related
behavior. They also found that prolonged stimulation of D2
receptors leads to inactivation of a regulatory protein called
Akt.

Furthermore, they showed, Akt inactivation occurred more
slowly and was maintained for longer than other similar
biochemical events that had previously been observed. However,
the mechanism behind that inactivation remained unclear.

In the current study in mice, the Duke team found that Akt
inactivation by dopamine involves the formation of a previously
unidentified complex containing beta-arrestin 2, Akt and a
third protein phosphatase 2A that inactivates Akt. Mice lacking
beta-arrestin become less responsive to certain drugs and
exhibit abnormalities in behaviors, such as locomotion,
associated with dopamine. In addition to the behavioral
deficits, the animals also lack normal regulation of Akt, they
report.

"These results provide direct physiologically relevant
evidence for the emerging concept that beta-arrestin 2 not only
controls desensitization but also participates in slow synaptic
transmission here by acting as a scaffold for signaling
molecules in response to dopamine receptor activation," Caron
said.

"The observations also provide an alternative pathway by
which dopamine receptor activation leads to the expression of
dopamine-associated behaviors."

The findings reveal another mechanism that could be targeted
for the treatment of schizophrenia and other psychiatric
disorders, the researchers said.

Further work is required to identify which
dopamine-dependent behaviors rely on each pathway. If the two
mechanisms control separate functions, particular drugs might
target some dopamine-related behaviors and not others, thereby
limiting the side effects of psychiatric therapy.

Akt also plays important roles in many other processes in
the body, including inflammation, cell death and the cell
proliferation that can spur cancer, the researchers added.
Therefore, similar mechanisms might also underlie other disease
pathways.

Collaborators on the study include Tatyana Sotnikova,
Sebastien Marion, Robert Lefkowitz and Raul Gainetdinov, all of
Duke. The work was supported by the National Institutes of
Health, the Human Frontier Research Program and the Canadian
Institutes of Health Research.