# Professor Peter Killeen discusses the importance of MAOI in tobacco addiction



## Alex (4/4/15)

Professor Peter Killeen discusses the importance of MAOI's in tobacco addiction...it's not just the nicotine.


The Smoking Gun

Peter R. Killeen (Killeen@asu.edu)

Gene and I would meet where the fence was down to the Lackawanna RR tracks, and head west along the rails two miles to high school. Some mornings I had the cigs; Camels or Luckys; sometimes he, Viceroys or Marlboros. A habit of boyhood companionship, carried into late night cramming in college, and through it to cope with the stresses of graduate school. Somewhere along the way it had become more than a habit. I smoked less for pleasure than to avoid the dis-ease of not. Like Mark Twain I found quitting easy: I had done it a half-dozen times.

Then I would cross the street mid-block to walk behind a smoker, inhaling deeply. To celebrate a week of abstinence, just one cigarette; and it was all over again. When we took our honeymoon in the Virgin Islands, my bride and I scored the limit of cheap cigarettes. Back home I looked at the plunder spread out on the bed. Knowing that a pack a day was no longer quite enough I calculated how soon they would be gone. Stepping back I saw, not the stack of cartons, but that I had become an addict. That was not a category I liked, but it was one that I could not deny. I could only make it untrue. I told her that I was going to quit. She looked at the cartons, and me; and wondered about my timing. "OK”, she said, ‘I will too. But this time you have to be serious; I can't keep doing this". This time, we kept each other honest. I never had that celebratory cigarette. I don't remember what happened to all those honeymoon cartons. I didn't think much about smoking over the decades since; becoming a professor in behavioral neuroscience focused on different issues, I had plenty on my plate.

Then I got a call from Washington, inviting me to a commission to craft a 'request for proposals'. This one was to ascertain why animal models of nicotine addiction did not predict of level of addiction or effectiveness of drug therapies to alleviate it. I pleaded ignorance of the issues, but they cited other useful skills I had, and thought a fresh look would be valuable. Viable models for screening candidate drugs would greatly reduce the cost of drug discovery; but no experiments to date were useful in finding drugs to help people quit smoking. A fresh look turned out to be very scary. Before getting on the plane, I talked to knowledgeable colleagues and graduate students, and crammed, once again, on literature. It was scary because I found very little evidence of addiction to nicotine! To tobacco? Of course. Nicotine? Nada. How could that be?

In 1988 the Surgeon General asserted that "Nicotine is the drug in tobacco that causes addiction". Throughout the report, however, he used the term nicotine addiction to stand for tobacco addiction--a synecdoche that would come to mislead many readers and even scientists. The American Psychiatric Association changed its DSM category from "Tobacco Addiction" to "Nicotine Addiction", even though nicotine replacement therapy did little to assuage withdrawal symptoms. All of the existing research on animal models was with nicotine, not the tobacco that people had such difficulty quitting. And even that research was strange. It was strange because rats are generally not very addictive creatures. You can get rats to lever-press for alcohol, but getting them to drink it takes cunning, and often the rats do it for the calories in the cocktail. This is not why most homo sapiens press the bar for booze.

But persistent experimenters such as Bill Corrigall found ways to get rats to lick or to inject alcohol. Cocaine was easier. Rats may prefer a good meal, but they will happily lever-press for coke. On the other hand, as the president of the Society for Neuroscience, Steven Hyman, noted, "it is difficult to argue that [drug self-administration by rodents] truly models compulsion [one of the Surgeon Generals' primary criteria for addiction in the above report], when the alternative to self-administration is solitude in a shoebox cage".

When rats are given options-- for instance of injecting cocaine or of licking a few drops of saccharine water--the majority of rats will stop injecting cocaine and simply satisfy their sweet tooth. Things went better with coke only when that was all that they had. Imagine what they would prefer if we took the lid off their shoebox. Nicotine? That is an even more interesting drug. Rats will lever-press for nicotine, but that also took some work to engineer. The trick was to announce the intravenous delivery of the nicotine with lights and tones.

That audiovisual enhancement initiated two decades of research on rats pressing levers for bright and noisy nicotine injections. Then one clever research team at the University of Pittsburgh put the nicotine injections on one lever and the flashing light switch on another.

To what we must imagine was their consternation, the rats much preferred to play with the lights than to inject nicotine. The investigators then pre-loaded the rats with nicotine, and with the glee and energy of a 5-year old with a kazoo, rats vigorously pressed for stimulation. Flashing lights that had been only of mild and desultory interest to the rodents became objects of their fascination once nicotine was on board.

Lights with nicotine--awesome; Fourth of July! Lights without nicotine--Fifth of July. How about nicotine without lights? Rats would inject it, grudgingly doing their owners a favor, but only at high doses. The experimenters concluded that nicotine is a weak primary reinforcer for rats, but could enhance the reinforcing effects of other stimuli. Well, peanut butter is a weak primary reinforcer for me. Not the stuffs of addiction for either of us. How about humans? Is nicotine addictive for them?

In one study a few smokers preferred to inject a mild shot of nicotine into their veins rather than injecting saline. The relevance of those results to your cousin's three thousand dollar cigarette addiction is somewhat less obvious than its relevance to the rats in those shoeboxes. Few junkies, after all, mainline nicotine--even as an appetizer. So why would people smoke cigarettes if not for Old Saint Nic?

There are 6000 possible answers to that question, the 6000 compounds that one can find in tobacco. Plus some subset of the 600 that the FDA has approved for addition to cigarettes, proprietary combinations used to give that longer, rounder, fuller, more satisfying flavor. One of the favorite remedies for cigarette addiction is--echoes of homeopathy--the application of nicotine--in a patch, or in gum, or in lozenges, or in nasal sprays, or in inhalers. The position of the medical community has always been that with these routes of administration, nicotine is not addictive; and has the significant advantage of being free of the sixty chemicals in cigarette smoke that cause cancer.

First, as we all know, our doctors are enjoined to do no harm: Nicotine is proffered as a remedy, not a scourge. Harmless at these therapeutic levels (but a potential tumor promoter at the levels found in cigs and e-cigs) and not addictive, they say; but of little help, they admit. Such applications raise the success rate in abstinence for a year by 10% in the best of cases. Like the rats given a choice between cocaine and sweet water, quitters would all, always, prefer a real cigarette over nicotine gum.

They chew instead only when they can maintain the resolve, and the gum gives them some solace but scant joy. So we rule out nicotine and start looking at the other ingredients. Divide and conquer is the strategy. What would a hoping-to-be-ex-smoker prefer: Nicotine without all the rest, or all the rest without nicotine? Then we could start parsing all the rest. We are both astoundingly lucky and astoundingly unlucky at the answer that we get to that first question. Jed Rose showed that neither IV nicotine, nor de- nicotinized cigarettes by themselves would make users stop wanting a real cigarette. But give them both of those at the same time, and craving stopped. We are lucky because the answer is quick and clear. We are unlucky because we don't know what to make of it.

Our subjects say, in essence "A pox on both of your houses!". De-nicotinized cigarettes quickly loose their attraction and are no cure for cigarette smoking. Nicotine without all the rest is at best a paltry cure for cigarette smoking. Like love and hate, all the action comes from the interaction: nicotine plus x. These results at once make things more complicated, but promise eventual simplicity. More complicated because the set of component combinations to test, even two-by-two, for interactive addictive capacity is astronomical. But the quest can be simpler because we know of one lead player, nicotine, and we know what it does in the brain.

We can start looking at suspects in the 6000-component line-up that are likely to have a synergistic effect. We don't have to look far or long, before a few shifty-eyed suspects stand out from all the rest. One of these is a gang whose tag is MAOI. To understand the interaction of nicotine and MAOIs you need to know the following: Both nicotine and MAOI affect the neurotransmitters, in particular a monoamine called dopamine. Among other roles dopamine mediates the pleasure/reward centers of the brain.

Such centers play a crucial role in learning, by reinforcing behaviors that achieve ends that are good for the organism. But once a signal has been sent that something you did is good, the neurotransmitters must be removed to get ready for the next pulse of information.

Several mechanisms do this. One is for the issuing cell to resorb it through a dopamine port. (Cocaine blocks this port and the resulting surge of dopamine is what gives such drugs their abuse liability.) Other members of the clean-up squads are chemicals that inactivate the monoamines by oxidizing them. These are the MAOs-the monoamine oxidizers. MAOIs inhibit them, and thus increase the amount of dopamine hanging around the signal junctions between neurons. There are a number of chemicals in cigarette smoke that act as MAOIs, and as their precursers. 

Joanna Fowler, Nora Volkow and their colleagues have shown that the brains of chronic smokers have substantially reduced levels of MAO. With the janitors laid off, the level of dopamine increases, and the brain compensates by becoming less sensitive to dopamine--it “down-regulates” by reducing its dopamine receptors. This take care of the immediate problem--the banks simply make it harder to cash in this coin. Like Gresham’s law--bad money drives good money out of circulation--the old neurotransmitters still floating around from yesterday's news drive the good ones (new signals of pleasure and success) out of circulation.

They are lost in the mix, and there are fewer dopamine receptors to cash them in anyhow. This makes for anxious, irritated, depressed and generally unhappy individuals, quickly on their way out the door for another pack. Nicotine arrives in the nick of time, and by stimulating nicotinic receptors on dopamine neurons, gives them the added kick they need. Now when signaling good news, they can get their head above water, over the higher threshold required to activate the reward neurons. Thus we have the dis-ease and cure, both in one round, firm, fully-packed injector.

A partnership made in ... or somewhere south of … heaven.

The effect of MAOI is long lasting. The numbers of dopamine receptors will take months to recover, and they may never get back all the way. Thus the lifelong hazard for relapse, for the one-just- for-old-times-sake indulgence that puts you back in bondage. Nicotine is not bad; but like a partner in a co-dependent relationship, its presence in tobacco makes the weed addictive.

A recent analysis of over 25000 individuals by scientists working at Pinney Associates estimated that the use of nicotine gum among adult never- smokers is 0 %. Among ex-smokers, that figure is 5 to 10%, and it was associated with a lower probability of cigarette use.

The jury is still out on the MAOIs. The brain is complicated, and many other suspects loiter in the halls. And this is all old news anyway: All the traffic seems to be heading elsewhere, down the road to rebadged head-shops to score and vape some of the cleaner, leaner alternative to combusted tobacco, e-cigarettes.

No question that e-cigs are less harmful than cigarettes; many fewer carcinogens, to start with. E-cigs are not quite lily white, as nicotine helps the build up plaque on arteries, and, by promoting the growth of new blood vessels nicotine is just what the doctor ordered to foster the growth of tumors, perhaps some of those that those carcinogens in cigarettes initiate. Now the cops are kerflummoxed. Do we prohibit something that is not completely healthy; or do we recognize that, as an alternative to cigarettes, it can save many lives? Do we choose purity; or do we choose harm- reduction?

If e-cigs displace cigarettes and help people quit other tobacco products --and they already have been shown to do this-- how do we justify discouraging their use? E-cigs contain no MAOI. Therefore, even though there is some dis-ease felt when quitting pure nicotine, e-cigs will not be addictive, we predict, and will not, without a lot of the usual will-power, suffice to cure cigarette addiction.

Wise voices, such as that of Sally Satel have argued convincingly that anti-smoking groups should endorse e-cigarettes and Snus (a form of oral tobacco much safer than regular cigarettes). Another young couple comes back from a honeymoon in the Bahamas having scored the legal limit of nicotine bottles of many flavors. Will he throw them on the bed, look at them in shock, and tell his incredulous bride "I am an addict and must quit"?

For months after will he risk jay-walking to inhale some second-hand vapor? Stay tuned folks, the Great American Experiment is under way.


source: https://www.academia.edu/11659347/The_Smoking_Gun--Memoirs_of_an_Addiction

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