Addicted to Nicotine
A National Research Forum

Section IV: Biology of Nicotine Addiction
Neil E. Grunberg, Ph.D., Chair

BRAIN CHEMISTRY AND IMAGING

Nora D. Volkow, M.D. (Contributors: J.S. Fowler, Y.-S. Ding, G.-J. Wang, and S.J. Gatley)
Medical Department
Brookhaven National Laboratory

Introduction

Positron emission topography (PET) is an imaging method uniquely suited to investigate the effects of drugs in the human and animal brain in a noninvasive way. PET uses radiotracers that bind selectively to the molecular targets for drugs, such as receptors, transporters, or enzymes that are involved in the synthesis and metabolism of neurotransmitters. This can be done at tracer concentrations that are devoid of pharmacological effects. Organic drug molecules can also be labeled with carbon-11 (C-11) by substitution of one of the stable carbon atoms. This does not change their pharmacological properties and enables the direct evaluation of their distribution and pharmacokinetics of the drug of interest in the brain. PET can also be used to assess the effects of drugs on brain glucose metabolism and cerebral blood flow, both of which can be used as markers of brain function.

Though few PET studies have assessed the effects of nicotine in the living brain, the following are some of the areas of investigation:

• Labeled Nicotine. Both natural (-)-nicotine and its enantiomers have been labeled with C-11. Higher uptake of (-)-nicotine was seen in the cortex, thalamus, and basal ganglia than in other regions, while levels of the unnatural enantiomers were lower. However, the kinetics of (-)-nicotine were not altered by administration of unlabeled nicotine, indicating that binding of nicotine is predominantly nonspecific. The poor-specific to nonspecific binding ratio has precluded its use as a tracer to monitor nicotine receptors in the brain.

• Nicotine Receptors. Nicotinic compounds with a high affinity for the nicotinic receptor have been developed to measure the distribution and concentration of nicotine receptors in the brain. One such compound is epibatidine, which has a high specificity for nicotine receptors (twentyfold more potent than nicotine) and little or no activity at other receptor types. The F-18 (t1/2 =3D 110 min)-labeled derivative of epibatidine showed very high-specific to nonspecific binding ratios in the human primate brain. This compound shows high-specific binding in the thalamus, which corresponds well with the high concentration of nicotine receptors in this brain region. The binding of epibatidine in the thalamus is almost completely blocked by pretreatment with nicotine. Unfortunately, epibatidine is very toxic, which has limited its use to investigation in nonhuman primates. Development of less toxic compounds will allow the performance of these studies in humans.

• Imaging of the Nicotine-Addicted Subject. In spite of the fact that there are 45 million cigarette smokers in the United States, little is known about the neurochemical actions of tobacco smoke on the human brain, and very few imaging studies have examined these effects. Glucose metabolic activity has been compared in a relatively small number of smokers and nonsmokers, with one study reporting slight elevations in metabolism and a second reporting no significant differences. The acute administration of intravenous nicotine has also been reported to reduce brain metabolism.

More recently, monoamine oxidase A and B (MAO A and B) have been examined in the human brain. MAO breaks down neurotransmitter amines like dopamine, serotonin, and norepinephrine, as well as amines from exogenous sources. It occurs in two subtypes, MAO A and MAO B, which can be imaged in vivo using =5B11C=5Dclorgyline and =5B11C=5DL-deprenyl-D2 and PET. Using these ligands, it has been shown that cigarette smokers have a reduction in brain monoamine oxidase B (MAO B) of about 40 percent relative to nonsmokers and former smokers. Smokers have a 28-percent reduction in brain MAO A, relative to nonsmokers.

Nicotine does not inhibit MAO B at physiologically relevant levels. MAO A and B inhibition is associated with enhanced activity of dopamine, a neurotransmitter involved in reinforcing and motivating behaviors and in movement as well as decreased production of hydrogen peroxide, a source of reactive oxygen species. Inhibition of MAO by cigarette smoke could be one of the mechanisms accounting for the lower incidence of Parkinson's disease in cigarette smokers. MAO A and B inhibition by smoke may also account for some of the epidemiological features of smoking, which include a higher rate of smoking in individuals with depression and addiction to other substances. In this regard, MAO A inhibitors are effective in the treatment of depression.

What We Know

• In addition to nicotine, cigarettes possess other pharmacological actions that may contribute to their reinforcing effects.

• Cigarette smoking inhibits the concentration of MAO A and B, and this inhibition recovers after cigarette discontinuation.

• There is a high concentration of nicotine receptors in the thalamus - a brain region involved with analgesia that may account for the analgesic properties of nicotine.

What We Need To Know More About

• Develop better ligands to monitor nicotine receptors in the human brain.

• Investigate the mechanisms responsible for MAO enzyme inhibition by cigarette smoking.

• Determine the half-life for inhibition of MAO A and B by cigarette smoking.

• Measure the levels of nicotine receptor occupancies achieved by doses of nicotine equivalent to those obtained when smoking a cigarette.

• Measure the levels of nicotine receptor occupancies required for the nicotine patch to be effective in preventing nicotine withdrawal.

• Evaluate the effects of chronic cigarette smoking on nicotine receptor expression in the human brain.

• Evaluate the effects of chronic cigarette smoking on other molecular targets in the brain.

Recommended Reading

Ding, Y.-S.; Gatley, S.J.; Fowler, J.S.; Volkow, N.D.; Aggarwal, D.; Logan, J.; Dewey, S.; Liang, F.; Carroll, F.I.; and Kuhar, M.J. Mapping nicotinic acetylcholine receptors with PET. Synapse 24:403-407, 1996.

Fowler, J.S.; Volkow, N.D.; Wang, G.-J.; Pappas, N.; Logan, J.; MacGregor, R.; Alexoff, D.; Shea, C.; Wolf, A.P.; Warner, D.; Zezulkova, I.; and Cilento, R. Inhibition of MAO B in the brains of smokers. Nature 379:733-738, 1996.

Fowler, J.S.; Volkow, N.D.; Wang, G.-J.; Pappas, N.; Logan, J.; Shea, C.; Alexoff, D.; MacGregor, R.; Schlyer, D.I.; Zezulkova, I.; and Wolf, A.P. Brain monoamine oxidase A inhibition in cigarette smokers. Proc Natl Acad Sci U S A 93:14065-14069, 1996.

Stapleton, J.M.; Henningfield, J.E.; Wong, D.F.; Phillips, R.L.; Grayson R.F.; Dannals, R.F.; and London, E.D. Nicotine reduces cerebral glucose utilization in humans. NIDA Res Monogr 132:106, 1993.

Volkow, N.D.; Rosen, B.; and Farde, L. Imaging the living human brain: Magnetic resonance imaging and positron emission tomography. Proc Natl Acad Sci U S A 94:2787-2788, 1997.