Smoking gun in nicotine addiction

The discovery, released today, of a new mechanism by which nicotine increases dopamine levels in the brain even hours after exposure may lead to a clearer picture of addiction and “better medications, with less side effects,” according to some addiction experts.

Neurobiologist Daniel S. McGehee and his colleagues at the University of Chicago have found that nicotine inhibits the release of the neurotransmitter GABA, which normally serves to turn off brain dopamine production. “This depression is due to the desensitization of the nicotinic receptors on the GABA cells,” McGehee told BioMedNet News.

Scientists have long known that nicotine, like most other addictive drugs, increases the production of dopamine in the reward system of the brain, which acts to reinforce behaviors critical to survival, such as drinking when thirsty or eating when hungry. Nicotine increases dopamine levels by mimicking the neurotransmitter acetylcholine (ACh), and binding to its receptor sites on dopaminergic neurons in the brain’s ventral tegmental area (VTA).

A single cigarette has enough nicotine to exhaust all the ACh receptors in the VTA within a few seconds, which left researchers puzzling to figure out why the levels of brain dopamine still continue to increase hours after a smoke. McGehee’s findings, which appear today in Neuron, may provide the explanation.

“They finally take us beyond common knowledge,” said Stephen Dewey, a neuroscientist at the Brookhaven National Laboratory. The new findings “clearly supports” research at BNL, where researchers have effectively treated the biochemical effects of all drugs of abuse by increasing the “outflow” of dopamine rather than just by inhibiting dopamine production.

Dewey is hopeful the next generation of drugs to treat nicotine addiction may include glutamergic and GABA compounds. The new knowledge should also be applied to behavior studies, because “addiction to nicotine is not just biochemical,” Dewey said.

McGehee’s findings build upon previous work that nicotinic receptors can increase the release of glutamate, another neurotransmitter that, like ACh, enhances dopamine production. The inhibition of GABA, however, is mediated by a different nicotinic receptor than the one responsible for enhanced glutamate release.

“The receptors on GABA neurons undergo desensitization more easily [with lower nicotine concentrations] than the ones that enhance glutamate release,” McGehee said. “We’re starting to get a clearer picture of how the profile of nicotine that a smoker experiences ultimately promotes dopamine release, which leads to the pleasurable or reinforcing effects.”

The new findings are “extremely important,” said John Dani, a neuroscientist at the Baylor College of Medicine. The next step, Dani said, would be to use intact animal models to understand the association between altering the circuitry and the consequent effects on behavior and decision-making.

Due to technical reasons, the researchers were forced to carry out experiments in young rats. “We know that nicotinic receptor expression varies over development, and very little drug abuse research has been carried out on rats at these young ages,” McGehee said. Continuing their GABA work on adult animals “will allow us to characterize the behavior of an animal and then test the
effects of nicotine.”

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