"As the negative health consequences of smoking have become more and more obvious, the majority of smokers have attempted to quit," says Marina Picciotto, PhD, of Yale University. "Unfortunately, people who want to quit often find that they cannot, and recent neuroscience research has identified many of the molecular mechanisms that lead to nicotine addiction.

"It is notable that many who smoke cigarettes have affective disorders, and many who have affective disorders such as major depression also smoke cigarettes and find it much harder to quit. We need new treatments for smoking cessation based on neuroscientific evidence and we need to understand the interaction between smoking and affective disorders so we can target new therapies to people who have the hardest time quitting."

Often, the depth of a person's addiction to nicotine can depend on their internal chemistry, says Jerry Stitzel, PhD, of the University of Colorado, who designed a study to evaluate the effects of nicotine over the course of a day.

Stitzel's team examined three types of mice: one with a genetic mutation that limits the conversion of the brain chemical serotonin to melatonin, a hormone made in response to darkness; one that produces melatonin but lacks the proteins essential for the brain and body to recognize it; and normal mice, used as the control group.

In mice that could make and recognize melatonin, injections of nicotine produced greater effects during the artificial 12-hour "day" in the controlled study environment than during the "night" portion of the study. In contrast, the normal reduction in the effects of nicotine was not observed during the night in mice that could make but not recognize melatonin. These results indicate that the reduced effects of nicotine at night are dependent upon the brain and body being able to recognize melatonin.

The role of melatonin in affecting the day-night differences in the effects of nicotine appears to depend upon the genetic makeup of the mice. In mice that could not make melatonin, day-night differences in the effects of nicotine could still be observed. Therefore, the day-night differences in nicotine's effects cannot be explained by the nighttime syntheses of melatonin in these mice. However, the daytime variation in the effects of nicotine corresponded to normal daily variations in blood levels of the stress hormone corticosterone.

"In most cases, the effects of nicotine we observed are greatest when corticosterone levels are at their peak," says Stitzel. This is notable since many smokers report that they smoke more when they are stressed.

Further research will continue to study the role of melatonin in altering the effects of nicotine and explore whether the correlation between levels of corticosterone -- a hormone known to be involved in the body's stress response -- and nicotine sensitivity is simply a coincidence or whether it helps to explain the differences in the effects of nicotine on the body and behavior over the course of the day. Understanding why the brain and body respond differently to nicotine during the day and at night might provide new targets for the development of therapies for those who want to quit.

In another animal study, Carlos Bolaños, PhD, of Florida State University focused on exposure to nicotine in adolescence and noticed profound differences in behavior, both immediately after exposure and in rats' long-term neurobiology.

Bolaños's data demonstrate that nicotine exposure during adolescence results in behavioral deficits indicative of a depressed- and anxiety-like state and that these nicotine-induced deficits can last into adulthood. This was true even for the rats that were taken off the nicotine between adolescence and adulthood.

A group of 30-day-old rats was exposed to three separate doses of nicotine twice daily for 15 days. For these lab animals, the period between the 30th and 45th days of life are adolescence. After exposure, the rats were divided into two groups: one in which behavioral testing began 24 hours after the last nicotine injection and one in which behavioral testing began two weeks later. Both groups of rats were studied for their reactions to an inescapable stressful environment, such as a swim test; a sucrose solution reward; and an anxiety test?being left alone in an open space.

Bolaños found that within 24 hours of the last nicotine exposure, rats were more sensitive to stressful situations. This tendency was found in both groups of rats. More specifically, the rats exposed to nicotine gave up when exposed to an inescapable stressful environment earlier than the non-nicotine exposed rats.

In addition, nicotine-exposed rats showed a decreased preference for a reward, a possible sign of their inability to experience pleasure. These rats also were less willing to explore new environments than the rats that had not been exposed to nicotine. When the rats were in the open-space test, they exhibited greater anxiety, indicated by a decrease in their exploration of their novel environment.

Although the mechanisms underlying these behavioral changes are unknown, the team is assessing the possibility that the effects are due to changes in signaling proteins in the mesolimbic dopamine system, the part of the brain which detects reward stimulus.

Further studies will probe the efficacy of serotonin uptake inhibitors, drugs commonly used to treat depression, on reversing these nicotine-induced behavioral deficits. In addition, further study is needed to see if nicotine exposure in adolescents plays a role in the development of disorders such as depression and anxiety, and whether substance abuse disorders appear at the same time.

In another new report, Jose Pardo, MD, PhD, and co-workers at the University of Minnesota and the Minneapolis Veterans Affairs Medical Center, found that the prefrontal cortex of the brain that reacts to nicotine cravings has an opposite reaction during a period of nicotine satisfaction.

In this study, a positron emission tomography (PET) scanner was used to track regional cerebral blood flow in addicted smokers during early withdrawal and just after the administration of a nicotine nasal spray. Seven participants each underwent three different conditions just before scanning, both before and after the nicotine was given. The scans occurred every 10 minutes.

One condition was the eyes-closed-rest status, in which the subject is in a relaxed state without specific task demands. The second was listening to a script about smoking cues, tailored to situations that induce the craving to smoke (e.g., describing a bar scene, smelling smoke, holding a cigarette). The third was listening to a script that was neutral or slightly pleasant (e.g., about a relaxed picnic).

During the scans, which lasted 90 seconds, the subjects in the cued states were told to close their eyes, to think about the cues, and to think about their emotional reaction to the cues. After the three conditions, they then received a nicotine spray. The three conditions were repeated after nicotine administration.

The study found that, regardless of visual cue or presence of pleasurable emotion before receiving the nicotine, the ventral and medial portion of the prefrontal cortex activated during withdrawal. Likewise, the same structure deactivated during the subject's period of nicotine contentedness. The opposite pattern was observed in the lateral portion of the orbital prefrontal cortex.

"This suggests that a neural network within the medial and lateral regions of the ventral prefrontal cortex modulates nicotine craving and satiety," Pardo says.

He notes that although previous studies have suggested this kind of modulation of craving and satiety in the prefrontal cortex during interoception, or sensitivity to internal stimuli, and exteroception (sensitivity to external stimuli), nicotine withdrawal alone can elicit such modulation. These regions were modulated by nicotine status even at rest, indicating that nicotine withdrawal alone, without cue-induced smoking cues, increases blood flow within the ventromedial prefrontal cortex, which provides sites in the brain that may underlie dependency on nicotine.

Similar brain activity elicited by nicotine, including reductions in regional blood flow in the ventral and medial prefrontal cortex, has been found in clinically depressed patients following antidepressant treatment. Of note, the antidepressant bupropion (Zyban or Wellbutrin) is used to treat nicotine addiction. Further study will be needed to gauge the extent to which these activations are specific to the experience of craving nicotine.

Read Montague, PhD, of Baylor College of Medicine, set out to answer whether nicotine addiction can affect decision-making: specifically, whether it can lead to confusion between two general classes of specific "guidance signals" in the brain. One set of signals is based on rewards that are actually experienced, called "experiential errors," and the other is based on outcomes that "could have been," called "fictive errors."

Montague found that both smokers and nonsmokers were strongly guided by rewards that are actually experienced. But the team also found that chronic smokers do not adjust their behavior based on what could have been, despite the clear presence of the fictive error signal identified in their brain activity.

Some substances, including nicotine, appear to inhibit decision-making. This is substantiated by the study's findings that smokers' choices are no longer guided by fictive error signals derived from what might have happened, but are instead guided by temporal difference (TD) error signals, used for habit learning and featured in computational models of addiction.

Montague created a gambling game for a group of 31 smokers and a control group of nonsmokers, monitoring their brain activity with a functional magnetic resonance imaging (fMRI) machine. Individuals in the group of smokers played the game under two separate conditions. In one, they smoked as usual, but under the other, the participants abstained from tobacco from midnight until the hour of their appointment.

The subjects viewed price histories from historical stock markets, then chose a proportion of an initial $100 investment to risk for the day. Once a decision was made, the subject received the next piece of information about the market: Depending on the market's activity, the investment was recorded as either a good one or one that could have been better. Using this game, Montague measured subjects' behavior and brain activity in response to both the guidance signals based on actual outcomes and those based on outcomes that could have been better.

The smokers tended to be insensitive to abstract situations like what could have happened (fictive outcomes) and instead listened only to the TD error signals. Acute smoking further enhanced both the neural TD signal and the impact of the error signal upon subjects' choices.

"These findings highlight the possibility that addiction may disrupt the balance between these two important guidance signals, so that the more abstract 'fictive error' is drowned out by the 'experiential error,' " Montague says. "The actual rewards take over, and the 'could-have-beens' no longer have a say in one's decision-making."

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