Besides the FDA, Congress and the courts have weighed in on tryingthe case of cigarettes as vehicles of nicotine addiction. Now anotherbranch of government, the Department of Energy's BrookhavenNational Laboratory (BNL), has apprehended in cigarette smoke apossible addictive co-conspirator with nicotine.
This alleged second perpetrator is an enzyme in the brain,monoamine oxidase B (MAO B). The smoking gun that indictedMAO B is an in vivo experiment conducted by Brookhaven chemistJoanna Fowler, and her associates, and announced in today's Nature.
"We've been interested in MAO B for many years," Fowler toldBioWorld Today. And we're also very interested in addiction here atBNL [in Upton, N.Y.]. So we've developed the tools for imaging theenzyme. While we were studying normal people, we happened to findthat the smokers among them had about a 40 percent decrease in thisenzyme."
Instead of the laboratory mice usually dragooned into smokingexperiments, Fowler recruited 20 human volunteers _ eight smokers,eight non-smokers and four recent quitters.
Her paper in Nature bears the title: "Inhibition of monoamine oxidaseB in the brains of smokers."
In the human brain, MAO B acts to break down dopamine. This near-ubiquitous busy-body neurotransmitter, which works on behavior andmovement in the central nervous system, is perhaps best known forits waning secretion in Parkinson's disease. In healthy people, MAOB keeps dopamine from over-secreting.
Another of dopamine's cerebral multi-purposes is the addiction-reinforcing job of signaling reward and pleasure sensations.
Something in cigarette smoke, and in the saliva of smokers, inhibitsMAO B, thereby stimulating the dopaminergic neurons. Itsmechanism, perhaps synergizing with nicotine, remains to beelucidated.
Smokers on average have half the risk faced by non-smokers ofcontracting Parkinson's. Few if any physicians urge cigarettes ontheir Parkinsonian patients. Instead, they prescribe L-deprenyl, anMAO B inhibitor, as an adjunct to the first-line anti-Parkinson'sdrug, levodopa. This chemotherapy aims to slow down progression ofthe disease by shoring up the wasting-away striatal dopaminergicneurons.
L-deprenyl, better known to doctors as selegiline, irreversibly bindsmonoamine oxidase by occupying the enzyme's catalytic site. Thedrug has a higher affinity for MAO B, than for the MAO A form,which mainly inhibits serotonin and norepinephrine, theneurotransmitters implicated in mood and depression.
Volunteers taking part in the BNL trial were healthy men and womenranging in age from 23 to 86. The eight smokers were consuming halfa pack to two packs a day. Averaging 46 years of age, they had beencigarette users for 24 years, on average
"The Brookhaven laboratory is a non-smoking building," Fowlerobserved. "A lot of employees volunteer for our positron emissiontomography [PET] studies."
As for the smokers, "We advertised for them. We just took smokersoff the street. "We didn't ask them to stop smoking."
MAO B Could Help Fight Addiction
Brain scans of the 20 subjects' MAO B by PET revealed thatsmokers average 40 percent less of the enzyme than non-smokers andex-smokers.
"The effect of cigarette on the enzyme is very strong," Fowler said."It jumps right out at you."
She suggested that "For those who smoke but want to quit, MAO Bcould one day be the target of specialized treatments." She also saidthat "to help people fight their addiction to tobacco and quit smoking,we need to develop a better understanding of why people smoke."
To visualize L-deprenyl as it chases down MAO B in the brain,Fowler and her co-authors labeled low doses of the drug with a short-lived radioisotope, which emits subatomic positrons, and injected itas an opaque visible tracer in their PET scans. She directs the PETprogram at Brookhaven.
To measure the degree to which cigarette smoking inhibits MAO Bcompared to its blockage by therapeutic doses of L-deprenyl, theygave one volunteer (a 43-year-old former smoker) a week-longregimen of medical-strength L-deprenyl. It decreased the enzymeinflux in his main brain regions by 86 percent.
Interestingly, a 31-year old active smoker _ up to two packs dailyfor 18 years _ had a similar influx level of the MAO B enzyme.
The fact that non- and ex-smokers had comparable MAO B levels,the Nature paper pointed out, "indicates that the differences in MAOB between smokers and non-smokers are due to pharmacological andnot genetic factors."
Since submitting their paper to Nature last year, Fowler and hergroup have "pursued some other aspects of their cigarette addictionstudy, with further human trials. We're looking for the effects ofsmoking on other systems," she observed, "and I have to sort the dataout before I can say what the effects are."
In a stop-press postscript to their paper, the BNL co-authors wrote:"It has recently been reported that the reversible MAO A inhibitormoclobemide facilitates the cessation of smoking in highly dependent[i.e., addicted] smokers." This work, she told BioWorld Today, wasreported by a French investigator, Ivan Berlin, last year in the Journalof Clinical Pharmaceutical Therapy.
Comment by two outside experts linked the MAO B connection toaddiction with the current concern over access to cigarettes by under-age customers. Psychiatrist Alexander Glassman, of ColumbiaUniversity in New York, and psychopharmacologist George Koob, ofthe Scripps Research Institute, in La Jolla, Calif., wrote in a Natureeditorial:
"If, in fact, cigarette smoking is able to further augment dopaminerelease through MAO B inhibition, and this contributes to increasingan individual's likelihood of addiction to other drugs of abuse[alcohol, cocaine, amphetamines, heroin], it would give aneuropharmacological basis to the proposal that cigarettes are a`gateway' drug. If this is true, it would raise even further the concernabout adolescent exposure to cigarettes." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.