Gene Variant Keeps Smokers Hooked by Weakening Key Brain Circuit

by Jim Schnabel

October 15, 2010

Some people who take up smoking can quit without great difficulty. But approximately half of smokers will not quit even if their habit starts to cause health problems such as lung cancer. Studies over the past few years have suggested that most of these “persistent smokers” possess variations in their genetic code that make it nearly impossible for them to quit, but it wasn't clear how. Now a team of researchers has reported that the gene variant most consistently linked to nicotine addiction is associated with a weakened connection or synchronization between two key brain regions.

“It is possible that the synchronization between these two regions is critical to balance inhibition with impulsivity, so that a reduced synchronization leads to a less controlled impulse to smoke,” says Elliot Hong, a psychiatrist at the University of Maryland School of Medicine who was first author of the study.

The report, which appeared July 19 in the early online edition of the Proceedings of the National Academy of Sciences, suggests that this brain circuit could soon be a target for anti-smoking treatments.

In the study, Hong and his colleagues, including researchers at the National Institutes of Health led by senior author Elliot Stein, looked for a particular variant of a gene known as CHRNA5 in 184 subjects—93 smokers, 79 non-smokers, and 12 ex-smokers. The gene codes for a fragment—the α5 subunit—of the nicotinic acetylcholine receptor (nAChR) on brain cells, to which nicotine molecules bind. Each nAChR is made up of a combination of five subunits (out of twelve possible subunit types), and those containing the α5 subunit are found only in certain parts of the brain.

The variant of α5 that the researchers looked for, known as Asp398Asn, was found in about 40 percent of the people in the sample. And of those who had inherited two copies of the variant (one from each parent), nearly all were smokers. The variant has even been linked to lung cancer, perhaps because it is so likely to hook people on the smoking habit. “The link between persistent smoking and this particular polymorphism of the α5 subunit gene has been replicated in many studies since its discovery in 2007,” says Hong.

Having established which of their subjects carried the smoking-linked variant of the α5 subunit, the researchers scanned their brains using a new functional magnetic resonance imaging (fMRI) technique known as resting-state functional connectivity fMRI. In the technique, subjects aren’t asked to perform a specific task, and the fMRI merely measures low frequency fluctuations in the activity of different regions—to see which regions’ activities are synchronized, and thus presumably connected.

Researchers were especially interested in the activity of the dorsal anterior cingulate cortex (dACC), a part of the cortex where nicotinic acetylcholine receptors containing the α5 subunit are relatively common. In research published last year, Hong and colleagues found that nicotine addiction is linked to the synchronization of the dACC with a set of limbic regions including the ventral striatum and nearby areas known as the “extended amygdala.” These limbic areas are involved in the emotional and motivational representations of things, such as liking and wanting, and researchers suspect that the dACC plays a role in modulating or inhibiting this limbic activity, thus helping to curb impulsive behavior.

In the current study, Hong and colleagues found that this same dACC-related circuit had a markedly lower functional connectivity in people with the smoking-linked α5 variant. Other dACC-related circuits were weakened in these subjects, but only the one linked to the ventral striatum/extended amygdala showed significantly more weakening in smokers versus non-smokers. Among smokers, the degree to which this connectivity was weakened also predicted the severity of addiction (measured by a standard smoking-persistence questionnaire). And the fact that even non-smokers with the α5 variant had a weakened connectivity in this circuit indicated that the effect was largely due to the gene, not to smoking itself.

“Previous research has shown that this α5 variant is associated with reduced nicotinic receptor function,” says Hong. He and others suspect that these desensitized α5-variant-containing receptors account for the weakening of circuit connectivity, which in turn could mean that the dACC is less able to moderate activity in the ventral striatum and extended amygdala—so that a person’s impulse to smoke becomes overwhelming. “But we don’t yet know the exact mechanism that lies beneath the correlation,” he cautions.

“The way that they have imaged changes in the connectivity between the cingulate down into the ventral striatum, and have shown how genetics can influence that, is really first class science—really cutting edge,” says Paul Kenny, a researcher at the Scripps Institute in Jupiter, Florida, whose lab also studies the α5 variant and other mechanisms of nicotine addiction.

Evelyn Lambe, a researcher at the University of Toronto whose lab recently published a paper on the α5 subunit’s possible role in attention, calls the results thought-provoking. A good follow-up, she suggests, would be to see whether the brains of α5 variant carriers and non-carriers respond differently while being exposed to smoking-related cues.

The same circuit is impaired by mental illness

The α5 variant appears to be only one factor that can weaken the connectivity of the dACC-ventral striatum circuit. Some of Hong’s subjects (about 45 percent) had mental illnesses such as schizophrenia, and they too showed a weakening of this circuit compared to healthy subjects, even though they had a normal incidence of the α5 variant. To Hong and his colleagues, the finding suggests that certain mental illnesses can affect the dACC-ventral striatum circuit through some other mechanism.

How to boost this circuit to help smokers kick the habit? One way would be to find a way to correct for the α5 variant, perhaps by a drug that boosts the function of α5-containing nicotinic receptors. “You would hope that by boosting these receptors, you could increase the circuit connectivity and thereby reduce a person’s vulnerability to tobacco dependence,” says Kenny.

Hong has wondered whether nicotine itself would work, if delivered in a less-addictive form such as a nicotine patch. But his group’s study last year found that while nicotine patches did boost circuits within the cortex—which may be related to nicotine’s transient cognition-enhancing effects—they did not significantly boost the connectivity of the dACC-ventral-striatum circuit that seems so important in addiction.

“We know that nicotine patches aren’t all that effective in helping people quit smoking,” says Hong. “One reason could be that nicotine doesn’t strongly affect that circuit.”