Eliminating protein in specific brain cells blocks nicotine reward

ScienceDaily (July 27, 2011) — Removing a protein from cells located in the brain's reward center blocks the anxiety-reducing and rewarding effects of nicotine, according to a new animal study in the July 27 issue of The Journal of Neuroscience. The findings may help researchers better understand how nicotine affects the brain.

Nicotine works by binding to proteins called nicotinic receptors on the surface of brain cells. In the new study, researchers led by Tresa McGranahan, Stephen Heinemann, PhD, and T. K. Booker, PhD, of the Salk Institute for Biological Studies, found that removing a specific type of nicotinic receptor from brain cells that produce dopamine -- a chemical released in response to reward -- makes mice less likely to seek out nicotine. The mice also did not show reductions in anxiety-like behaviors normally seen after nicotine treatment. Smokers commonly report anxiety relief as a key factor in continued smoking or relapse.

"These findings show that the rewarding and anxiety-reducing properties of nicotine, thought to play a key role in the development of tobacco addiction, are related to actions at a single set of brain cells," said Paul Kenny, PhD, an expert on drug addiction at Scripps Research Institute, who was unaffiliated with the study.

Previous studies showed blocking the alpha4 nicotinic receptor within the ventral tegmental area (VTA) -- a brain region important in motivation, emotion, and addiction -- decreases the rewarding properties of nicotine. Because alpha4 receptors are present on several cell types in the VTA, it was unclear how nicotine produced pleasurable feelings.

To zero in on the circuit important in the brain's response to nicotine, researchers developed mice with a mutation that left them unable to produce the alpha4 receptor, but only on dopamine brain cells. Mice lacking alpha4 receptors in these cells spent less time looking to obtain nicotine compared with normal mice, suggesting the alpha4 receptors are required for the rewarding effects of nicotine. Nicotine also failed to reduce anxiety-like behaviors in the mutant mice, as it normally does in healthy mice.

"Identification of the type of nicotinic receptors necessary for two key features of nicotine addiction -- reward and anxiety -- may help us better understand the pathway that leads to nicotine dependence, and potential treatment for the one billion cigarette smokers worldwide," McGranahan said. Diseases from tobacco use remain a major killer throughout the world, causing more than 5 million deaths per year.

The findings could guide researchers to a better understanding of the mechanisms of tobacco addiction and assist in the development of new drugs to treat tobacco addiction and provide relief from anxiety disorders, Kenny added.

The research was supported by the National Institute of Neurological Disorders and Stroke, the National Institute on Alcohol Abuse and Alcoholism, and the National Institute on Drug Abuse.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Society for Neuroscience, via EurekAlert!, a service of AAAS.

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Workings of brain protein suggest therapies for Fragile X Syndrome and autism

ScienceDaily (July 21, 2011) — Researchers now have a much clearer understanding of how mutations in a single gene can produce the complex cognitive deficits characteristic of Fragile X Syndrome, the most common inherited form of intellectual disability. As the majority of patients with Fragile X Syndrome also display autism-like symptoms, the findings offer hope for treating both conditions.

A report in the July 22nd issue of the journal Cell, published by Cell Press, defines a set of messenger RNA (mRNA) molecules that the Fragile-X mental retardation protein (FMRP) binds in the brains of mice. Many of these mRNAs encode proteins that function at neurons' connection points. When properly bound, FMRP prevents the translation of these mRNAs into proteins until the time is right.

"By understanding for the first time the direct targets of FMRP and its actions, we open up a whole world of potential avenues for therapies designed to make kids with Fragile X or autism better," said Robert Darnell, a Howard Hughes Medical Institute investigator at The Rockefeller University.

"The power comes from taking two diseases with similar symptoms and looking at what is in common," added Jennifer Darnell, also at The Rockefeller University. Of the almost 850 identified targets of FMRP, she explained, it is likely only a much smaller subset has a real impact on health or disease.

The Darnell team's breakthrough uses a technique they developed a few years ago based on a "biochemical trick." They use ultraviolet light to solidify the bonds between a protein, in this case FMRP, and the mRNAs it binds. Those protein-mRNA complexes could then be isolated and sequenced to reveal a "beautiful map" of the mRNA transcripts and precisely where they are bound to FMRP.

The experiments reveal that FMRP specifically binds to the protein-coding portions of those brain mRNAs. Jennifer Darnell said that distribution is unlike what they've seen before and looked much like the distribution of ribosomes, the cellular components that assemble proteins.

Further experiments suggest that FMRP acts as a "brake," reversibly stalling ribosomes after they bind mRNA. Robert Darnell likened FMRP to the nozzle at the end of a hose. It allows the mRNA transcripts to be loaded with ribosomes in the locations where they will be needed, and when the time is right, bursts of translation (protein synthesis) can occur. That sort of tight control is likely to be critical for the formation and plasticity of neural connections, the cellular foundation for learning and memory.

Their basic scientific discoveries suggest two different overall strategies for treating Fragile X Syndrome: by lowering the activity of particular proteins normally kept under wraps by FMRP or by replacing FMRP's ability to stall ribosomes. Notably, the Darnells say the latter is exactly what antibiotics do to slow the growth of bacteria.

"We may be able to take the edge off of the extra protein synthesis," Jennifer Darnell said.

Ultimately, there will be more to the story, Robert Darnell added. "FMRP is one of many regulatory proteins in the neuron. It doesn't work all by itself."

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Cell Press, via EurekAlert!, a service of AAAS.

Journal Reference:

Jennifer C. Darnell, Sarah J. Van Driesche, Chaolin Zhang, Ka Ying Sharon Hung, Aldo Mele, Claire E. Fraser, Elizabeth F. Stone, Cynthia Chen, John J. Fak, Sung Wook Chi, Donny D. Licatalosi, Joel D. Richter, Robert B. Darnell. FMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and Autism. Cell, 2011; 146 (2): 247-261 DOI: 10.1016/j.cell.2011.06.013

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Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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