Cigarettes are among the most addictive agents known. However, tests with laboratory animals suggest this may not be the effect of nicotine alone, but that one or more of the other constituents in tobacco smoke may be interacting with nicotine to boost its addictive properties. Some of those other constituents inhibit the brain-cell enzyme monoamine oxidase (MAO). MAO metabolizes neurotransmitters, including dopamine, which is associated with reinforcement and reward. Inhibition of MAO increases levels of dopamine, and brain scans have shown significantly reduced levels of MAO in smokers.
To test whether MAO inhibition increases nicotine reinforcement, Shahrdad Lotfipour, Ph.D. and his associates compared the behavior of lab animals given an MAO inhibitor, tranylcypromine (TCP), to that of animals given saline. They found that the TCP-treated MAO-inhibited animals showed a significant preference for sniffing at nose pokes with nicotine as opposed to the saline-treated animals. They also found that the brains of the TCP-treated MAO-inhibited animals showed significant enhancement of nicotine-modulated dopamine activity. Research suggests that other constituents of tobacco smoke like norharman (a beta-carboline with biological and potential toxicological activity), which inhibit MAO and influence brain dopamine release, may exhibit similar brain and behavior effects as tranylcypromine, thus influencing tobacco addiction.
In other studies, Dr. Lotfipour has been working to sort out how prenatal exposure to maternal cigarette smoking influences the brain and behavior of adolescent offspring. Children of mothers who smoked during pregnancy are at risk for fetal under-nutrition, lower birth weight, delayed development and sudden infant death syndrome, in part due to deficits in neurotransmitter release. Effects in childhood or adolescence include ADHD, substance abuse and obesity. Nicotine is known to bind to so-called nicotinic receptors to modulate dopamine release. Nicotinic receptors are present during development, and experiments have shown that offspring of rodent mothers pretreated with nicotine show a strong preference in adolescence for self-administering higher doses of illicit drugs.
Recent evidence has suggested that the alpha-6 nicotinic receptor subunit is critically involved in the modulation of dopamine release in the striatal regions of the brain, and that this could influence drug reward. The alpha-6 subunit is present in utero, and it peaks in its expression during adolescence. Dr. Lotfipour collaborated with Canadian researchers on a study involving 600 adolescents. Among them, prenatal exposure to maternal cigarette smoking was a significant predictor of their substance use. The researchers found a genetic marker that appears to increase risk for those who were exposed to smoke in utero.
Shahrdad Lotfipour, Ph.D.
2003, 2010 NARSAD Young Investigator Grantee
Department of Psychiatry
University of California, Irvine