Some people smoke a few cigarettes now and then, while others smoke 30, 40, or more per day. NIDA-supported research now suggests that smokers' differences in tobacco consumption reflect, in part, differences in the functional efficacy of one subtype of nicotinic acetylcholine receptor (nAChR).
The new animal research, by Dr. Paul Kenny and colleagues at Scripps Research Institute in Jupiter, Florida, indicates that the nAChR subtype that incorporates the α5 structural subunit (termed α5* nAChR) promotes an aversive state in response to nicotine that increases in strength as blood concentrations of the drug rise. Among the evidence: Eliminating the α5 subunit greatly increased the amount of nicotine that animals would self-administer.
The new findings may explain previous observations that people who have a gene variant that results in a less functional version of α5* nAChR are far more likely to become dependent on nicotine than those with the normal version. The results open up the possibility that medications to stimulate the activity of α5* nAChRs might help smokers smoke less, reducing their risk for addiction and other consequences of exposure to tobacco.
A Tale of Two Pathways
As anyone who has inhaled tobacco for the first time has experienced, nicotine's effects are not all rewarding; some can be extremely unpleasant. A smoker's motivation to light up depends on the balance between anticipation of the rewarding effects and aversion to the noxious ones. The balance tilts more toward aversion as nicotine concentrations in the blood rise.
Dr. Kenny's team theorized that each smoker's rate of tobacco consumption depends on his or her tipping point, and that the tipping point, in turn, depends on how strongly two opposing brain pathways respond to nicotine. One, the reward pathway, which links the ventral tegmental area (VTA) to the nucleus accumbens (NAc), responds to nicotine stimulation by generating pleasurable feelings and motivation to repeat the experience. The other, the medial habenula-interpeduncular pathway (MHb-IPN), encodes states of aversion, thereby opposing the effects of the VTA-NAc reward systems and limiting further nicotine intake.