What does nicotine actually do? Need help for research proposal...

[satsumas]

Hey guys,
I'm writing a research proposal involving smoking cessation and writing my section on nicotine vs, other stems. I'm not a scientist but believe I may be able to get some money to fund some small scale highly speculative research in the area of smoking cessation. I've been reading the literature the past few weeks but thought I'd start a thread on this awesome board to get some additional commentary going.

From what I can tell, though nicotine has widespread actions in the brain and peripherally, nicotine is not in itself all that reinforcing or hedonic. It seems that it takes significant effort to get animals to self administer, and giving nicotine patches to ex smokers, then withdrawing them. Does not cause readdiction to cigarettes. And of course we don't see teenagers hanging outside Walgreens begging adults to buy them Nicolette's. But nicotine does stimulate vta dopaminergic neurons and light up the nacc like other more addictive drugs of abuse. So what gives?

What I have read seems to say that what nicotine does is enhance the reinforcing value of other stimuli, help to give it rewarding valence. So things like the ritual of smoking, the airway sensations of nicotine (which seem to be important), the smell, the psychosocial reward, now these things have been made far more reinforcing via nicotines actions in the nacc. Is this an accurate understanding? How then do the maoi constituents of smoke play into this?

I'm writing my section comparing nicotine to other stimulants like cocaine, amphetamines, and methylphenidate. Im a little confused though, as these substances light up the mesolimbic dopamine circuit even more strongly than nicotine, yet none of these serve as effective substitute or treatments for nicotine dependency. My understanding of addiction science is very weak, and I know the cellular effects are different which may be the reason, but I find it odd that amphetamines do not treat nicotine dependency, as they are even more rewarding would in some sense "swamp" the nacc with dopamine....how does this not serve as an effective substitute for nicotine reward? And it actually seems as though giving stimulants noncontingently dosent treat nicotine dependency, it actually makes people smoke more! What is going on here? It seems bupropion and nortrp are effective stimulating treatments for smoking and lower reward thresholds that are raised in withdrawal, but amphetamine is not an effective treatment, why?

Thank you so much for any insight here. I am continuing to read as much as I can but do not have access to non pubmedcentral papers and have only checked out a few books from ucsf library and they haven't answered these specific questions...also any good recent papers about smoking in general that are of importance, or anything else relating to nicotine dependency that might be useful for me to check out, I'd sure love some references.

Thanks so much, I will post my proposal on this board when I'm finished as I'd love some comments....

 

[polymath]

Nicotine acts by binding to nicotinic acetylcholine receptors (on brain cells and neuromuscular junction), which are ion channels and when acutely activated, lead to neuron firing because of depolarization of the cell membrane. When the neurons have been exposed to nicotine for some time, the persistent depolarization makes the neuron unresponsive to more nicotine/acetylcholine and prevents neuron firing(an effect opposite to the initial).

Only the acute effect increases dopamine in the nacc, which means that you have to get the nicotine concentration in your brain to rise rapidly to experience a "nicotine high". This is why inhaling tobacco smoke is addictive but the slow release from a nicotine patch is not.

The two phase effect of nicotine on neurons makes it more complicated that other drugs of abuse. For instance, administering a nicotine antagonist to someone who's nicotine-dependent does not cause precipitated withdrawal (compare naloxone for an opiate-dependent person). In fact nicotine antagonists can help make the nicotine withdrawal LESS intense.

Amphetamine does not substitute for nicotine, because the mechanism of nicotine withdrawal is more complicated than just a decreased dopamine level in nacc.

 

[Ampa-omega]

i saw your thread at MnM, im reading it right now

 

[kaskelot]

Tobacco smoke doesn't just carry nicotine. Substituting nicotine is easy, bringing along the effects of MAOI-type is not.

 

[ProducedRaw]

Tobacco smoke doesn't just carry nicotine. Substituting nicotine is easy, bringing along the effects of MAOI-type is not.

Surely it's as simple as taking an MAO-B inhibitor. I've had success with using Rhodiola Rosea, an MAO-A and B inhibitor, to treat nicotine withdrawal associated depression.

 

[Nagelfar]

Also, smoking nicotine is seen to be more reinforcing with amphetamine rather than less due to smoking's mechanism of increasing dopamine levels being cumulative with the mechanism of amphetamines to dopamine: meaning it is a potentiator. It doesn't just flood out the same dopamine pathways and 'swamp' the effect as you term it.

 

[kaskelot]

Surely it's as simple as taking an MAO-B inhibitor. I've had success with using Rhodiola Rosea, an MAO-A and B inhibitor, to treat nicotine withdrawal associated depression.

Together with nicotine substition (swedish tobacco pouches for oral use) it was no good for me, even in very small doses of Rhodiola extract. Perhaps my daily intake of coffee might have been an issue as well.

Over all, MAOI:s are a bad mix with many medicines and sometimes also with common food. It's not as simple as buying nicotine patches or tobacco for oral use.

 

[ProducedRaw]

Together with nicotine substition (swedish tobacco pouches for oral use) it was no good for me, even in very small doses of Rhodiola extract. Perhaps my daily intake of coffee might have been an issue as well.

Over all, MAOI:s are a bad mix with many medicines and sometimes also with common food. It's not as simple as buying nicotine patches or tobacco for oral use.

Coffee actually contains MAO-A and B inhibitors too. I imagine that it causes dopamine levels to crash on the comedown which would probably increase evening cravings. I should add that I was vaporising my nicotine in an electronic cigarette, which causes it to hit the bloodstream at the same rate as smoking does.

 

[negrogesic]

As 'non-smoker', I recently attempted to become 'addicted' to nicotine using electronic cigarettes, and despite 6 months of daily usage of 'high' nicotine content liquids, I was unable to develop any meaningful dependency (granted, I may have felt a touch of 'something', but nothing consistent with tobacco discontinuation syndromes). When smoking the electronic cigarette, I would often get questions from 'actual' smokers about how effective the e-cigarette was as a cessation aid/smoking replacement (to which I would reply, "I wouldn't know; i've never been a smoker"). Understandably, people were rather bewildered with this answer, as they assumed I must have been addicted to cigarettes. I have smoked cigarettes in the past, but I simply did not experience an 'effect' that justified their continued use. I actually preferred the electronic cigarette in terms of psychoactive effect. I found that with long, continuous inhalations of the vapor, I was able to create a sedating-narcotic effect without the nausea/dizziness generated from a similar use of cigarette (or the 'i've just been poisoned' feeling I encountered when experimenting with tobacco 'snuff'). I should note that I view tobacco and alcohol as 'drugs', and consequently, I attempt to derive 'drug-like' effects without consideration to social and other less tangible aspects of their use. From my perspective, tobacco lacks significant/distinctive psychoactive effects when in cigarette form, and while powerful, the snuff feels more like a poison than a 'drug worth abusing'. In other words, much unlike alcohol, it seems rather difficult to get 'high' using tobacco products without getting ill.

I am not trying to suggest that nicotine is not addictive when administered 'alone', but my experience seems to underscore the significant 'reinforcing' disparities between tobacco and 'nicotine'. Am I willing to smoke actual cigarettes for 6 months in order to further explore this disparity; no.

 

[Amu]

negrogesic, my experience was similar to yours, I found no benefits from smoking tobacco nor did I find it psychologically addictive, and considering the cost and harms, I don't see the appeal of smoking. My guess is that similar to the self-medication hypothesis, people who have low endogenous chemicals that tobacco seems to normalize will experience more severe addiction, thus maybe why people who are psychotic smoke tobacco so often. Nicotine definitely functions as an agonist at several types of nicotinic acetylcholine receptors as well as causing up-regulation (http://www.ncbi.nlm.nih.gov/pubmed/17997038), it's MAO inhibiting properties also raise levels of DA/NE/SER thus having beneficial properties against certain conditions.

 

[SpunkySkunk347]

Also, smoking nicotine is seen to be more reinforcing with amphetamine rather than less due to smoking's mechanism of increasing dopamine levels being cumulative with the mechanism of amphetamines to dopamine: meaning it is a potentiator. It doesn't just flood out the same dopamine pathways and 'swamp' the effect as you term it.

I've found smoking tobacco to be highly uncomfortable while on amphetamine, or coming down from it.
I put this off to vascular damage and hypertension caused by amphetamine being exacerbated by tobacco.

I have found smoking tobacco to be the most reinforcing with opiates and alcohol rather than amphetamine. I have actually quit smoking cigarettes several times because of amphetamine -- not only because of the compounded negative physical effects from mixing the two, but also because cigarettes seemed to ruin the euphoria of amphetamine.
If I smoke a cigarette while waiting for my amphetamine to kick in, the positive mental effects will be dampened or even absent when the amphetamine finally does kick in.

 

[negrogesic]

negrogesic, my experience was similar to yours, I found no benefits from smoking tobacco nor did I find it psychologically addictive, and considering the cost and harms, I don't see the appeal of smoking. My guess is that similar to the self-medication hypothesis, people who have low endogenous chemicals that tobacco seems to normalize will experience more severe addiction, thus maybe why people who are psychotic smoke tobacco so often. Nicotine definitely functions as an agonist at several types of nicotinic acetylcholine receptors as well as causing up-regulation (http://www.ncbi.nlm.nih.gov/pubmed/17997038), it's MAO inhibiting properties also raise levels of DA/NE/SER thus having beneficial properties against certain conditions.

The thing is, with effort. I can derive some pleasure from nicotine vapor and tobacco. But this pleasure takes considerable effort on my part in such a fashion to make their use illogical. I would however recommend a trial of nicotine patches (to be worn over night), as the dreams experienced are rather astonishing to the non-smoker.

Yet, having experienced severe opioid addiction in the past (along with heavy experimental abuse of virtually all drugs of abuse), I was personally somewhat surprised that my efforts to toy with nicotine addiction (albeit, vapor) failed to 'compel'....

 

[sekio]

negrogesic, have you ever tried hookah? I think that for lack of a better term a delicious delivery system is key to achieving a good state of intoxication. Or dependence - I read somewhere that some sultans would rather go without food than without hookah...

 

[Dr.Shopper]

I don't smoke, but I use smokeless tobacco. I have noticed that although I am addicted to the chemical aspect, the actual physical action of using tobacco is half of the addiction. Because of the elevated mood and sense of calm and focus that nicotine (used to) give me, my brain automatically associates the feeling of a simple bulge in my lip with positive feelings. Whenever I try to quit nicotine, I find that using a non-nicotine herbal snuff seriously reduces my perceived withdrawal symptoms. So I think it is safe to say that the physical action of using tobacco products is a very large part of the addiction, which is why things like patches do not work for many people. I also believe that a large reason for why it is so hard for me to quit for a long period of time is that in using tobacco, it has developed into my body's natural method of coping with everyday stress and anxiety. Because of this, I feel that my mind has sort of abandoned any "natural" means of coping with stress. I do not get any positive feelings from nicotine anymore, but what keeps me coming back is that feeling itself of the action of dipping or chewing. Although I do experience withdrawal from nicotine itself when I abstain, I believe the mental aspect is HIGHLY overlooked. I believe that if the average tobacco addict's cigarettes or snuff were replaced with a nicotine free product that smelled, tasted, and looked exactly the same, a great number of them wouldn't even notice the difference.

 

[Dr.Shopper]

And I would just like to add that I am not an occasional tobacco user, I dip ten or more times a day every day, and this has been going on for two years. Any questions at all, feel free to ask.

 

[negrogesic]

negrogesic, have you ever tried hookah? I think that for lack of a better term a delicious delivery system is key to achieving a good state of intoxication. Or dependence - I read somewhere that some sultans would rather go without food than without hookah...

Naturally, the answer is yes (there are few drugs/routes I haven't tried). And certainly, the hookah appeared to be the most agreeable method to smoke tobacco, with a far smoother and prolonged 'buzz'. After getting somewhat bored/frustrated when friends would take me to establishments that employ such devices as a main 'feature', I found it difficult not to 'spice things up' with a little marijuana (frowned upon due to odor), a ball of crude opium/tar heroin, or the odd chunk of cocaine base. Of course, all friends attached to said hookah gave prior consent to the introduction of said 'additives'. On an entirely unrelated note, I am reminded of an old adage: "Impropriety is the spice of life".

Back to the point at hand - I have yet to get more than a 'buzz' from tobacco. I can recall many descriptions of the psychoactive qualities of tobacco smoke from those addicted, and the word 'high' was rarely mentioned. However, a synonym of sorts, "buzz", is used commonly. Yet, I suppose many of those deemed 'alcoholic' may not word the use the 'high' in their characterization of the psychoactive effect. Yet I believe most of use here can agree that etoh is truly a euphoriant that produces a 'high'.

All said and done, I am somewhat certain that had I attempted a 6 month trial of 'real' cigarettes (as opposed to my 6-month electronic cigarette trial), I would be discussing the rich, full-bodied flavor in an rationalization/justification of the 'finer qualities' of cigarette addiction. There have been many studies regarding nicotine/tobacco addiction, but it would be interesting to see some that involve a controlled and intended creation of cigarette addicts in human subjects who have never smoked. Countless studies abound that involve the already addicted, but few involve 'lab-made' addicts of cigarettes.

 

[Starshowers]

Well yes, the habit itself (oral fixation) is the addictive part.

 

[Renz Envy]

negrogesic, have you ever tried hookah? I think that for lack of a better term a delicious delivery system is key to achieving a good state of intoxication. Or dependence - I read somewhere that some sultans would rather go without food than without hookah...

The only time I found myself addicted to nicotine was with hookah.

I can smoke cigarettes for a week straight, I have been a "social smoker" for 3 years, but I have never bought a package of cigarettes for myself.

However hookah was a completely different story. The euphoria I experienced from inhaling large amounts of smoke was incredible. I have experienced a "pins and needles" effect covering my entire body during the first few sessions I had whilst under the slight tinge of alcohol. This experience is known to be one of excitement.

Perhaps I am different, but hookah seems to me like a completely different substance.

 

[Geaux Tigers!]

I found it difficult not to 'spice things up' with a little marijuana (frowned upon due to odor), a ball of crude opium/tar heroin, or the odd chunk of cocaine base.

Negrogesic, you're by far my favorite poster on this forum. I read your posts on Advanced Drug Discussion all the time. I simply lack the knowledge you do to discuss these topics; however, I love your educated insight and the fact that you're a medical doctor. I bet you're serious when it comes to your job, e.g. throwing mirtazapine as an FU drug and not prescribing stimulants like crazy. I love that fact that you've tried everything under the sun.

I'd seriously hang out with you. I'd smoke "whatever" out of that hookah with you!

I know this is off-topic but I had to say something. I hope it's not creepy.

 

[clubberdude]

I'm not sure if this is exactly what you are looking for, as its an anecdotal observation.

I find nicotine to be probably about as physically addictive as Amphetamine (or there abouts, i.e. moderately addictive). However, it seems to have a very high level of psychological addiction. Firstly, you associate certain activities with smoking so it kind of maps into these activities. Secondly, the craving seems to me as though it is a result of the very-fast-feedback one gets from smoking which appears to be the re-inforcing factor in my experience.

Interestingly, MPA (a dopamine-norepinephrine releasing agent similar to amphetamine) substitutes well from a physical standpoint for Nicotine. This suggests that Nicotine must have at least some activity on the Dopamine system (I've not researched it to any real degree). Also, isn't Bupropion (a Dopamine-Norepinephrine antagonist of sorts) prescribed for smoking cessation? Apparently this drug can be relatively successful in smoking cessation, adding weight to the Dopamine-Norepinephrine mechanism for Nicotine's activity.