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Crazy Cravings May Be Genetic

Individual brain chemistry and genes could be the key to understanding why some people become addicted to nicotine, University of Colorado at Boulder researchers say.

The depth of a person’s addiction to nicotine appears to depend on his or her unique internal chemistry and genetic make-up,  said lead author Jerry Stitzel, an assistant professor in CU-Boulder’s department of integrative physiology and researcher with CU-Boulder’s Institute for Behavioral Genetics.

It’s also why the chemical compound’s effects appear to diminish at night, said Stitzel, who presented his team’s findings in San Diego last week during the Neuroscience 2007, an annual scientific meeting.

Stitzel and his team set out to evaluate the effects of nicotine over the course of a day by examining mice that could make and “recognize” melatonin, a powerful hormone, and others that could not.

Scientists believe that melatonin, which is produced by darkness, tells our bodies when to sleep. The CU researchers found that the reduced effects of nicotine at night were dependent on the mice’s genetic make-up, and whether their brains and bodies were able to recognize melatonin.

Crave ImageThey also found that the daytime effects of nicotine were greatest when levels of the stress hormone corticosterone were high.

The second finding could explain why many smokers report that the first cigarette of the day is the most satisfying.

Cortisol, the human equivalent of corticosterone, is at peak levels in the early morning, Stitzel said.

“The negative health consequences of smoking have become well known, and a large majority of smokers say that they would like to quit,” Stitzel said. “As such, we need to understand the interaction between smoking, genes and internal chemistry so we can target new therapies to those who have a hard time quitting.”

While the team’s research could shed light on why people smoke, Stitzel says more research is needed to determine the role that melatonin plays in altering the effects of nicotine, and whether the correlation between higher corticosterone levels and nicotine sensitivity is a coincidence.

Researchers from Yale, Florida State, the University of Minnesota and the Baylor College of Medicine also presented findings based on research into the effects of smoking and nicotine.

Source: Colorado Daily

Two Nicotine Addiction Puzzles Explained

The stranglehold of nicotine addiction leads to more than four million smoking-related deaths each year. Scientists at the California Institute of Technology have now explained two roots of that addiction. The discoveries may offer new hope not just for smokers, but eventually also for sufferers of Parkinson’s disease, a debilitating movement disorder that affects some 40 million people worldwide.

Researchers have known for decades that chronic exposure to nicotine increases the number of nicotine receptors–molecules that are activated by binding to the drug–on nerve cells. The binding of nicotine to these receptors, and in particular to one specific subunit known as alpha4, enhances the release of a pleasure-causing neurotransmitter called dopamine.

But “this increase is confusing,” says Henry A. Lester, the Bren Professor of Biology at Caltech, “because for opioid addiction, and for many other classes of addictions and of drugs in general, the body attempts homeostasis and adjusts the number of receptors downward if there is a constant stimulus.” Understanding this paradox–how it is possible that smokers become tolerant to the pleasurable effects of nicotine despite the fact that their brains produce new nicotine receptors in response to the chemical–is crucial for defeating nicotine’s addictive power.

Lester, his postdoctoral researcher Raad Nashmi, and their colleagues at Caltech, the University of Colorado at Boulder, and the University of Pennsylvania School of Medicine, have now solved the mystery, by developing a special mouse strain with fluorescent nicotine receptors. These fluorescent tags allowed the scientists to monitor the effects of the nicotine throughout the brain, down to the level of individual neurons.

“We find that alpha4 containing receptors, those with some of the highest sensitivity to nicotine, are upregulated”–or increased in number–“by chronic nicotine in a cell-specific fashion,” Lester explains. “In particular, the alpha4-containing receptors are indeed upregulated in the dopamine-producing portions of the brain, but not in the dopamine neurons themselves.” Instead, the increase in receptor number occurs only in neurons that inhibit dopamine neurons–a group called the GABAergic neurons.

Dopamine FormulaThis surprising result led the researchers to conduct experiments with delicate electrical probes. In chronic nicotine-treated mice (and presumably in chronic smokers), the dopamine neurons are chronically inhibited from firing in the absence of nicotine. And nicotine itself still excites the dopamine neurons, leading to pleasure, but much less than expected.

“This research explains tolerance during nicotine addiction,” Lester says. “Once in a while, an important piece of a puzzle does fall into place.”

“This is outstanding work that will open the door to further studies of nicotinic receptor upregulation in the cognitive and rewarding effects of nicotine,” comments Daniel S. McGehee of the University of Chicago, who studies the neurobiology of nicotine addiction. McGehee was not involved in the present research.

But there’s more. In the special Caltech mice, the largest number of new nicotine receptors appeared in the mouse forebrain. This is the part of the brain involved in cognition. Electrical measurements showed that these new receptors also helped to boost synaptic transmission. The result may explain why many smokers claim that cigarettes actually help them think better–and why 44 percent of the cigarettes smoked in the United States are consumed by people with mental health problems.

“People may attempt to medicate themselves with nicotine, and my research is also aimed at trying to understand the mechanism behind that,” Lester says.

“We now think that we need to concentrate on drugs that manipulate upregulation.” Lester adds. His lab is currently developing simpler cell-based systems using the fluorescently labeled nicotine receptors. Using special microscopes, the effect of particular drugs on those receptors can be monitored.

One long-term benefit of the research could be the development of better therapies for Parkinson’s disease, the chronic neurological condition that gradually destr