Dopamine Imbalances Cause Sleep Disorders In Animal Models Of Parkinson's Disease And Schizophrenia

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.