Manipulating Dopamine in a Bid to Help Smoking Addicts

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In what could be hopeful news for the treatment of smoking addiction, Parkinson's disease, and schizophrenia, researchers at the California Institute of Technology have discovered a new target for fighting diseases that result from extreme levels of the hormone and neurotransmitter dopamine.

A research team led by Caltech scientists Henry Lester and Ryan Drenan, along with colleagues from the University of Colorado at Boulder, the Rockefeller University, the University of Utah, and the pharmaceutical company Targacept, genetically modified a specific type of brain receptor to increase its sensitivity to both nicotine and acetylcholine -- another of the brain's neurotransmitters.

When the receptor - which is found primarily on neurons that produce dopamine - comes into contact with its biochemical matches nicotine or acetylcholine, the neuron starts to pump out dopamine.

Earlier research had examined the reverse scenario -- what happens when you block the receptor's function and stop dopamine production? -- but this was the first study to investigate what occurs when the receptor becomes more sensitive and accordingly floods the system with dopamine.

Even low doses of nicotine charge up the receptors, prompting the neurons on which they are grouped to unleash a torrent of dopamine. This flooding was obvious when the researchers observed the behavior of mice who carried the genetically modified receptors: Because dopamine plays a crucial role in movement, the mice immediately and suddenly became hyperactive; the researchers wrote that this phenomenon "could be useful in understanding the causes of human hyperactivity such as that observed in ADHD."

The scientists also noted that the receptors seem to be especially important in what is known as the mesolimbic pathway - a control for dopamine production that is involved in the addictive properties of nicotine. The research team has already begun to explore the targeting of these receptors with specific drugs, potentially providing a new way to treat nicotine addiction and, perhaps, other dopamine-related conditions, including ADHD, Parkinson's disease, and schizophrenia.

"By uncovering the biological role of these receptors, especially with regard to their role in the midbrain dopamine system, we show that they are excellent drug targets," said Drenan.

The paper, "In Vivo Activation of Midbrain Dopamine Neurons via Sensitized, High-Affinity a6* Nicotinic Acetylcholine Receptors," was published in the Oct. 9 issue of the journal Neuron, supported by funding from the National Institutes of Health, the Moore Foundation, the Croll Research Foundation, California's Tobacco-Related Disease Research Program, a Caltech alumnus, and the Howard Hughes Medical Institute.

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