Researchers observe brain circuit activation, rapid receptor occupation.

BY LORI WHITTEN, NIDA Notes Staff Writer

One difference between a smoker and an ex-smoker is that the latter has successfully overcome cravings for tobacco. To learn how people achieve this feat, NIDA-funded researcher Dr. Arthur Brody has been looking inside the brains of would-be quitters. His findings, based on three separate imaging studies, indicate that when smokers actively resist cravings, they engage brain areas that focus attention and regulate emotion; that heavy smokers can stave off craving only by keeping virtually all nicotinic receptors in the brain filled; and that nicotine is the only component of cigarette smoke that occupies these receptors.

SMOKING SATURATES RECEPTORS As nicotine from a cigarette attaches to the α4β2*-nACh nicotinic receptors in the brain, it displaces a radiolabeled tracer (red and yellow indicate high levels of the tracer, green indicates intermediate levels, and blue indicates low levels). The nicotine from three puffs displaced 75 percent of the tracer from study participants' receptors, and the nicotine from three cigarettes, nearly all.

PATTERNS OF RESISTANCE

In one study, Dr. Brody and his colleagues at the University of California, Los Angeles charted the changes in cerebral activity that accompanied willful resistance to videotaped smoking cues. One of the changes, intensification of activity in a specific brain area, parallels the effects of bupropion, suggesting that the anti-smoking medication may reinforce cognitive strategies that people naturally implement when they try to quit. Other specific brain activity changes identified in the study may provide leads for developing new medications and behavioral treatments for smokers.

Dr. Brody enlisted 42 men and women from the community at the Greater Los Angeles Veterans Affairs Healthcare System. On the morning of the study, each participant smoked a final cigarette and, 25 minutes later, put on a pair of special goggles to watch short video clips during brain scanning. The clips introduced the viewer to everyday situations—driving, writing a letter, standing outside a building. Two of every three clips also featured images that commonly incite nicotine craving, such as a view of someone taking out a lighter, preparing to light a cigarette, or actually smoking a cigarette. The researchers asked the participant to record the intensity of his or her craving, while either passively experiencing it or actively resisting it. The participants said that they usually resisted smoking cues by trying to distract themselves or ignore thoughts of smoking.

In the absence of smoking cues, the participants reported an average craving intensity of 2.4 out of a possible 5. The intensity rose to 3.0 when they saw a smoking cue. The intensity of the craving was similar whether or not the participants resisted the urge to smoke.

The researchers collected functional magnetic resonance images (fMRI) of the participants' brains while they were watching the videos. During efforts to resist smoking, activity increased in the dorsal anterior cingulate cortex (DACC) region, which participates in focusing attention and controlling emotions, as well as decisionmaking and planning, conflict avoidance, and error detection. Dr. Brody suggests that this DACC activation may reflect the participants' struggles to direct their attention away from cigarettes. Other researchers have noted intensified DACC activity when individuals employ specific trains of thought to try to control their emotional responses to anxiety-provoking stimuli. Engaging this area repeatedly may strengthen the neural circuit and bolster smokers' ability to resist cigarettes.

Dr. Brody and colleagues were intrigued by other changes in brain activity that occurred when their study participants resisted smoking cues. Among these were increased activity in the posterior cingulate cortex (PCC), which processes emotions and related sensory information, and in the precuneus, which has been related to consciousness of self.

Simultaneously, the team observed decreased activity in the lateral occipital and right postcentral gyri (LOG and RPG); the LOG deals with visual input and the RPG modulates movement. Changes in these areas had not been previously observed in the context of smoking cessation and so may provide new clues to the cognitive and emotional dynamics that accompany that effort.

Taken together, these findings suggest that actively resisting the urge to smoke involves a redistribution of neural activity from sensory and motor areas of the brain to those that mediate rewards and emotions.

SMOKING'S DRAMATIC EFFECTS ON RECEPTORS

In another study that underscores the challenge of quitting, Dr. Brody's team charted relationships between smoking, craving, and nicotinic receptors. They found that heavy smokers crave nicotine whenever the drug occupies less than 95 percent of the most common nicotinic receptors, the α4β2*-nACh subset, in the brain. Smoking just a few puffs goes a long way toward saturating these receptors, which are the primary sites where nicotine attaches to brain neurons and exerts its psychoactive and physiological effects.

Although scientists have known that stimulation of these receptors underlies nicotine addiction, newly developed radiotracers have helped them measure receptor occupancy much more accurately and connect it to craving and other symptoms of withdrawal.

The 11 volunteers who took part in this study had smoked for 18 years, on average, and were currently smoking a pack a day. On the day of the study, following 2 days of abstinence, the participants smoked and reported their intensity of craving as the researchers used positron emission tomography (PET) imaging to observe α4β2*- nACh receptors.

The images revealed that smoking occupied α4β2*-nACh receptors throughout the brain with striking completeness, and for several hours. After the first puff, nicotine occupied one-third of the receptors; after the third puff, 75 percent; and after a full cigarette, 88 percent. As receptor occupancy increased, the participants' craving decreased, until—generally after 2.5 to 3 cigarettes—they achieved complete relief at about 95 percent occupancy.

"Our findings show how many receptors are taken up by nicotine," says Dr. Brody. "My colleagues and I were surprised that just one puff started to fill the receptors so substantially."

The team's findings suggest that some of the behaviors that characterize nicotine addiction may be explained by smokers' need to maintain receptor saturation. "Many smokers say they must have a cigarette to get their day going, which makes sense because receptor occupancy would be quite low after waking," says Dr. Brody.

Although near saturation of nicotinic receptors relieves craving, nicotine dependent people smoke beyond this point. Moreover, Dr. Brody notes that "blood levels of nicotine that accompany replacement therapies, such as the patch or gum, would likely saturate the receptors, yet only 20 to 25 percent of smokers on this treatment stay abstinent for a year." These observations suggest that other factors also drive smoking.

EVIDENCE OF OTHER FACTORS

To separate the impact of nicotine from other aspects of smoking—including the more than 4,000 chemicals other than nicotine in cigarette smoke—Dr. Brody and colleagues conducted a third study. The investigators followed a procedure that paralleled the one they had used to track the impact of smoking on α4β2*-nACh receptors. Again, they charted the relationships between smoking, craving, and nicotinic receptors—this time in response to cigarettes with only a trace amount of nicotine.

The 15 volunteers who took part in this study had smoked for 14 years and were currently smoking 19 cigarettes a day, on average. In two sessions, each after 2 days of abstinence and separated by at least a week, they participated in PET imaging scans and reported their intensity of craving. On one study day, the participants smoked a denicotinized cigarette. On the other study day, seven participants did not smoke, and eight smoked a low-nicotine cigarette.

The images revealed that smoking a denicotinized cigarette, which contains only about 4 percent of the nicotine in a regular cigarette, resulted in a 26 percent occupancy of nicotinic receptors, compared with 79 percent after a low-nicotine cigarette (half the nicotine content of a regular cigarette), and no occupancy among those not given any cigarette. The 26 percent occupancy by smoking a denicotinized cigarette was predicted based on the amount of nicotine present.

This study demonstrates that of all the chemicals found in cigarette smoke, nicotine is responsible for virtually all α4β2*-nACh receptor occupation, the researchers note. These findings also demonstrate that smoking a cigarette with only a trace amount of nicotine leads to substantial receptor occupancy in the brain.

Although smoking a denicotinized cigarette had a smaller impact on nicotinic receptors compared with the effects of a low-nicotine or regular cigarette, it did lessen craving. Before they smoked, the participants reported an average craving intensity of about 5 (on a scale of 0 to 6); these reports fell to 3.6 and 2.4 for those smoking a denicotinized and low-nicotine cigarette, respectively. This accords well with findings of prior studies indicating that denicotinized cigarettes reduce the urge to smoke. The taste, smell, and feel of cigarette smoke in the mouth contribute to smoking's appeal, Dr. Brody says, and denicotinized cigarettes do provide these sensory experiences. Additional factors, such as stress and the perceived pleasure of smoking, also may play a role.

These findings elucidate why it is so difficult to give up cigarettes, according to Dr. Brody. "The many effects of smoking, including elevated mood and alleviation of anxiety, suggest that a long-term smoker may face considerable biochemical, cognitive, and emotional readjustments when he or she quits," says Dr. Brody.

Dr. Ro Nemeth of NIDA's Division of Clinical Neuroscience and Behavioral Research adds that inhalation is the fastest way for any drug to reach the brain. "The connection between a puff on a cigarette and the positive feelings it quickly generates helps maintain smoking, even when people know its negative consequences and want to quit," Dr. Nemeth says.

SOURCES

Brody, A.L., et al. Brain nicotinic acetylcholine receptor occupancy: Effect of smoking a denicotinized cigarette. International Journal of Neuropsychopharmacology, published online 2008. [Abstract]

Brody A.L., et al. Neural substrates of resisting craving during cigarette cue exposure. Biological Psychiatry 62(6):642-651, 2007. [Abstract]

Brody, A.L., et al. Cigarette smoking saturates brain alpha 4 beta 2 nicotinic acetylcholine receptors. Archives of General Psychiatry 63(8):907-915, 2006. [Full Text]

Volume 22, Number 2 (December 2008)