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Dopamine Imbalances Cause Sleep Disorders in Animal Models of Parkinson’s Disease and Schizophrenia

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Duke Health News 919-660-1306

DURHAM, N.C. -- Neuroscientists at Duke University Medical
Center working with genetically engineered mice have found that
the brain chemical dopamine plays a critical role in regulating
sleep and brain activity associated with dreaming.

When dopamine levels were dramatically reduced, the mice
could no longer sleep, the scientists said. When dopamine
levels were increased, the mice exhibited brain activity
associated with dreaming during wakefulness.

The same processes likely occur in humans, according to the
researchers. They said the findings give insight into the sleep
problems common among patients suffering from Parkinson's
disease, a neurodegenerative disorder in which brain cells
containing dopamine die or become impaired.

"Our study may lead to development of new diagnostic tools
for the early detection of Parkinson's disease based on the
sleep disturbances that are often associated with motor
symptoms of the disease," said senior study investigator Miguel
Nicolelis, M.D., Ph.D., Anne W. Deane professor of
neuroscience.

The findings may also provide a mechanism to explain some of
the symptoms, such as hallucinations, experienced by psychotic
and schizophrenic patients, he said.

The researchers published their findings in the Oct. 11,
2006, issue of the Journal of Neuroscience. The work was
supported by the National Institutes of Health, the Hereditary
Disease Foundation and the Anne W. Deane professorship to
Nicolelis.

Parkinson's disease occurs when the brain cells, or neurons,
that normally produce dopamine die or become impaired. Once 60
percent to 70 percent of the neurons are knocked out of
commission, the jerky movements and fixed facial expressions
characteristic of Parkinson's appear.

The new study suggests that destruction of significantly
fewer dopamine-producing cells could result in sleep problems
long before the motor problems become apparent, the researchers
said.

Dopamine is a "neurotransmitter" that carries signals from
one neuron to another. It is known to control movement,
balance, emotion and the sense of pleasure.

Normally, when a signal needs to travel through the brain,
neurons release dopamine to transport the signal across the
gap, or synapse, between neurons. A kind of protein pump,
called a transporter, recycles dopamine back to the neurons to
prepare for the next burst of signal.

In studies 10 years ago, Marc Caron, Ph.D., James B. Duke
professor of cell biology and a co-investigator in the current
study, used the techniques of genetic engineering to produce a
strain of mice that lacked this protein transporter. In such
transgenic mice, dopamine lingers outside brain cells,
stimulating surrounding neurons hundreds of times longer than
normal. Caron and colleagues found that when they placed the
mice in an unfamiliar environment, such as a new cage, the
animals groomed themselves excessively and ran around the cage,
mirroring the bizarre behaviors experienced by people with
schizophrenia.

The researchers used this same strain of transgenic mice in
the current study. They reasoned that both schizophrenia and
Parkinson's disease are characterized by imbalances of dopamine
in the brain, and that patients with both diseases experience
sleep disturbances. So the researchers sought to further
manipulate the mice to study the role of dopamine in the sleep
cycle.

First, the researchers treated the mice with a chemical that
stops the production of dopamine entirely. In fairly short
order, the mice had used up their initial supply of dopamine
and were running on empty.

The mice became rigid, immobile, and unable to sleep or
dream, displaying symptoms similar to those experienced by
patients with Parkinson's disease, the researchers said.

The researchers then measured the electrical activity in
each animal's hippocampus, the region of the brain known to be
involved in emotion and memory, during three major brain
states: wakefulness, quiet sleep and dreaming (also known as
rapid eye movement sleep). Using electrodes finer than a human
hair implanted into individual neurons, the researchers could
monitor signals passed among hundreds of neurons in the treated
mice. They found a lack of dopamine completely suppressed brain
activity and behaviors associated with quiet sleep and
dreaming.

To verify that the sleep disturbances were caused by a lack
of dopamine, the researchers gave the mice L-dopa, a drug used
to increase the levels of dopamine in Parkinson's disease
patients. The treated animals regained the brain patterns and
behaviors associated with sleep and dreaming, demonstrating the
critical role dopamine plays in the sleep-wake cycle, according
to the researchers. Further pharmacological testing revealed
that L-dopa exerted its effects by docking at a specific site,
called the D2 receptor, on the surface of the neurons.

"Sleep disorders may be the first sign of Parkinson's
disease," said lead study investigator Kafui Dzirasa, an
M.D.-Ph.D. student working in Nicolelis's laboratory.

"By further studying the sleep patterns in animal models of
Parkinson's disease, we hope to come up with a sleep diagnosis
test that could detect the early signs of the disease years
before the major symptoms appear," he said.

The study also provided insights into the biology underlying
schizophrenia, the researchers said. They found that the excess
dopamine in the brains of the mice generated patterns of brain
activity that made it look as though the animals were
experiencing brain activity associated with dreaming when they
were actually awake.

"One of the preeminent ideas of classical psychiatry is that
people who had hallucinations, such as schizophrenics, were
actually dreaming while they are awake," Nicolelis said. "Our
results give some initial biological evidence for this
theory."

Other researchers who participated in the study were Sidarta
Ribeiro, Rui Costa, Lucas Santos, Shih-Chieh Lin, Andres
Grosmark, Tatyana Sotnikova and Raul Gainetdinov.

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