Question re: MAO effects of Nicotine

[protovack]

I used to be a heavy smoker and have tried to quit before. I've quit probably 5-6 times, each time around a week. I quit two weeks ago and this time my goal is permanent abstinence. I experienced the classic withdrawal symptoms in the first three days, and now after two weeks I'm getting lingering symptoms, mainly light depression and inability to concentrate.

I've heard that it takes two weeks for acetylcholine receptor levels to normalize after nicotine sensitization. But I don't know too much about the MAOI effects. The information I found seems contradictory though.

I found this article:
http://www.ncbi.nlm.nih.gov/entrez/...uids=11694206&query_hl=12&itool=pubmed_docsum

"Platelet monoamine oxidase, smoking cessation, and tobacco withdrawal symptoms."
From ABSTRACT: Results showed that smoking behavior, indexed by expired air carbon monoxide levels, was negatively correlated with platelet MAO-B activity prior to smoking cessation. Moreover, MAO-B activity significantly increased by approximately 100% at 4 weeks after quitting smoking. However, little or no recovery occurred within the first week of abstinence, suggesting that the constituents in tobacco responsible for MAO inhibition may have half-lives of several days.

My interpretation of this is that I am still deficient in MAO-B activity. How does this square with my symptoms of depression and inattentiveness?

But wait a second...
http://www.ncbi.nlm.nih.gov/entrez/...uids=16177026&query_hl=15&itool=pubmed_docsum

Monoamine oxidase inhibition dramatically increases the motivation to self-administer nicotine in rats.

Guillem K, Vouillac C, Azar MR, Parsons LH, Koob GF, Cador M, Stinus L.

Laboratoire de Neuropsychobiologie des Desadaptations, Unite Mixte de Recherche 5541, Centre National de la Recherche Scientifique, Universite de Bordeaux 2, 33076 Bordeaux Cedex, France.

Nicotine is the major neuroactive compound of tobacco, which has, by itself, weak reinforcing properties. It is known that levels of the enzymes monoamine oxidase A (MAO-A) and MAO-B are reduced in the platelets and brains of smokers and that substances, other than nicotine, present in tobacco smoke have MAO-inhibitory activities. Here, we report that inhibition of MAO dramatically and specifically increases the motivation to self-administer nicotine in rats. These effects were more prominent in rats selected for high responsiveness to novelty than in rats with low responsiveness to novelty. The results suggest that the inhibition of MAO activity by compounds present in tobacco smoke may combine with nicotine to produce the intense reinforcing properties of cigarette smoking that lead to addiction.

I don't really understand these results. So nicotine is an MAOI, but MAO inhibition by another route actually increases the amount of self-administration of nicotine? Where is the causal relationship here?

Hmmmm....
http://www.ncbi.nlm.nih.gov/entrez/...uids=11343627&query_hl=15&itool=pubmed_DocSum

Monoamine oxidases and tobacco smoking.

Berlin I, Anthenelli RM.

Department of Pharmacology, Pitie-Salpetriere University Hospital, Paris, France. [email protected]

Although nicotine has been identified as the main ingredient in tobacco responsible for aspects of the tobacco dependence syndrome, not all of the psychopharmacological effects of smoking can be explained by nicotine alone. Accumulating preclinical and clinical evidence has demonstrated that smoking also leads to potent inhibition of both types (A and B) of monoamine oxidase (MAO). Smokers have 30-40 % lower MAOB and 20-30 % lower MAOA activity than non-smokers. Reduced MAO activity in smokers has been shown by direct measures (platelets, positron emission tomographic studies) or by indirect measures (concentration of monoamine catabolites in plasma or CSF). We examine the hypothesis that chronic habitual smoking can be better understood in the context of two pharmacological factors: nicotine and reduced MAO activity. We speculate that MAO inhibition by compounds found in either tobacco or tobacco smoke can potentiate nicotine's effects. Based on this concept, more effective anti-smoking drug strategies may be developed. As a practical consequence of tobacco smoke's MAO-inhibitory properties, comparative psychiatric research studies need to screen and control for tobacco use.

Can anybody shed some light on this?

 

[BilZ0r]

Nicotine releases dopamine; MAO metabolises dopamine; MAO inhibition potentiates dopamine release caused by nicotine and hence potentiates self-administration.

Smoking inhibits MAO. How this effects depression or attention; I don't know.

I've heard that it takes two weeks for acetylcholine receptor levels to normalize after nicotine sensitization

That doesn't sound right to me... but it could be.

 

[Dr. Beat]

I have read alot about nicotine, and from what i have read, Nicotine is NOT an MAOI. Example, if you chew nicotine gum or use patches, your MAO are unchanged.

In cigarette smoke, i remember them saying 'harmalines', which are very strong MAOI's, in small doses in each ciggarette, that lower your MAO-A and MAO-B

and i think that cigarette smoke contains beta-carbolines (also in FRIED FOOD) that are MAO inhibitors - that is why FRIED FOOD taste much better than Boiled/Steamed Food.

This site contains alot of info about this www.waisays.com

Drugs are everywhere.......

 

[bigmac74]

In cigarette smoke, i remember them saying 'harmalines', which are very strong MAOI's, in small doses in each ciggarette, that lower your MAO-A and MAO-B

I thought beta-carbolines only inhibited MAO-A, not MAO-B? (according to erowid.)

and i took a quick check on the site and found this:

Cigarette smoke contains physically addictive beta-carbolines, and so does prepared food.

To me this instantly triggers propaganda, as i'm fairly certain that beta-carbolines aren't physically addictive.

and i think that cigarette smoke contains beta-carbolines (also in FRIED FOOD) that are MAO inhibitors - that is why FRIED FOOD taste much better than Boiled/Steamed Food

Oh come on, the amount of time it takes for the beta-carbolines to reach your brain should be long after you've eaten the food, so this makes no sense.

 

[protovack]

So am I reading this correctly: nicotine *itself* is not an MAOI? It is another molecule in the smoke (harmalines)?

 

[Dr. Beat]

So am I reading this correctly: nicotine *itself* is not an MAOI? It is another molecule in the smoke (harmalines)?

yes, that is what i read on www.acnp.com and 2 other good sites.

 

[Dr. Beat]

I thought beta-carbolines only inhibited MAO-A, not MAO-B? (according to erowid.)

and i took a quick check on the site and found this:


To me this instantly triggers propaganda, as i'm fairly certain that beta-carbolines aren't physically addictive.



Oh come on, the amount of time it takes for the beta-carbolines to reach your brain should be long after you've eaten the food, so this makes no sense.

beta-carbolines are addictive - try eating NO beta-carbolines for 1 week and see how long you last - only eat steamed/boiled food all week - no processed food at all (like cereal). Example boiled meat/veg/rice for 1 week and see how long you last. Modern food is full of drugs and are VERY addictive.

Just because you cannot see it, does not mean it is not true....

But i am sure you know everything already, so why am i bothering to tell you ?

 

[Smyth]

From what I gather (and this is not an indepth pharmacological account) is that nicotine works directly on the nAChR's and this triggers DA/NA as a secondary effect. In other words indirect mechanism.

 

[BilZ0r]

Probably even more indirect than that... desensitization of tonically active nicotinic receptors on GABAergic interneurons in midbrain dopaminergic nuclei... as these receptors become less active, reducing GABAergic activity... While nicotine does have a direct effect on dopaminergic neurons, this effect passes within a couple of minutes because of desensitization, but dopamine release lasts for many minutes.

The theory is supported by the fact that dopaminergic neurons express nicotinic Alpha7 homomers, and gabaergic interneurons express alpha4beta2 containing receptors.... and knocking about alpha7 does nothing to nicotine self-administration, but knocking about alpha4 prevents it.

 

[bigmac74]

beta-carbolines are addictive - try eating NO beta-carbolines for 1 week and see how long you last - only eat steamed/boiled food all week - no processed food at all (like cereal). Example boiled meat/veg/rice for 1 week and see how long you last. Modern food is full of drugs and are VERY addictive.

Just because you cannot see it, does not mean it is not true....

But i am sure you know everything already, so why am i bothering to tell you ?

I'm not going to argue, since I have not done any research into it, and it is possible you are right, but why do people extract harmaline from syrian rue et cetera when they can get it from cooking oil (or whatever it is your talking about).

Also, you lied about harmalines inhibiting MAO-B, so how do I know you are not lying what ever else you say?

Also, what sort of amounts of beta-carbolines are there in our cooked food?


EDIT: PMed you, found something else

http://www.ncbi.nlm.nih.gov/entrez/...ve&db=PubMed&list_uids=14611187&dopt=Abstract

Tetrahydro-beta-carboline alkaloids occur in fruits and fruit juices. Activity as antioxidants and radical scavengers.

 

[BilZ0r]

OI!!! Leave your processed food paranoia arguements out of this thread

 

[5-HT2]

^^^I second that

 

[5-HT2]

Probably even more indirect than that... desensitization of tonically active nicotinic receptors on GABAergic interneurons in midbrain dopaminergic nuclei... as these receptors become less active, reducing GABAergic activity... While nicotine does have a direct effect on dopaminergic neurons, this effect passes within a couple of minutes because of desensitization, but dopamine release lasts for many minutes.

The theory is supported by the fact that dopaminergic neurons express nicotinic Alpha7 homomers, and gabaergic interneurons express alpha4beta2 containing receptors.... and knocking about alpha7 does nothing to nicotine self-administration, but knocking about alpha4 prevents it.

It's actually more complicated even than that. High-affinity (presumably alpha4beta2) nAChRs are expressed on striatal axon terminals of dopamine neurons as well as on the cell body. At high firing frequencies, the short-term facilitation of neurotransmitter release caused by calcium entry through nAChRs overrides the inhibitory effects of nAChR desensitization, and thus nicotine's effects act as a high-pass filter to enhance dopamine release induced by phasing firing and decrease what is induced by tonic firing.

As a side note, I think you meant beta2 and not alpha4, because AFAIK nothing has been published on self-administration in alpha4 KO or KI's yet.

 

[BilZ0r]

^ You sure you're not thinking of how cholinergic neurons in the striatum act during physiological rewards?


I'm basing my theory on

Mansvelder HD, Keath JR, McGehee DS. Synaptic mechanisms underlie
nicotine-induced excitability of brain reward areas. Neuron. 2002 Mar
14;33(6):905-19.

But yeah, you're right about the beta2 thing.

 

[protovack]

At high firing frequencies, the short-term facilitation of neurotransmitter release caused by calcium entry through nAChRs overrides the inhibitory effects of nAChR desensitization, and thus nicotine's effects act as a high-pass filter to enhance dopamine release induced by phasing firing and decrease what is induced by tonic firing.

Interesting. Could you maybe explain this a little more? I've heard of the phasic/tonic model for dopamine regulation but I really don't know enough to understand it.

 

[5-HT2]

First I should provide links to the studies I mentioned 1,2.

Bilz0r and I provide complementary, convergent explanations based on electrophysiological studies in slices of different brain areas. Bilz0r is right on with his explanation of how the cells shift to phasic mode (except for what he says about receptor expression), but due to the presence of alpha4beta2 nAchRs on dopamine axon terminals, this alone can not explain why there is such a substantial and long-lasting increase of dopamine release in the accumbens/striatum. That's where the studies I cite come in, showing that nicotine as well as partial antagonism of nAChRs reorganize release probability so that the axons release less dopamine from a single pulse, allowing them to release more from subsequent pulses provided that enough calcium is present and there are enough readily releasable vesicles left, which only occurs under conditions where there is both high-frequency firing and calcium influx through desensitized nAChRs.

 

[BilZ0r]

Maybe... I like my story better... though I suppose your story makes better physiological sense.

 

[5-HT2]

Maybe... I like my story better... though I suppose your story makes better physiological sense.

I don't think they conflict at all, as I was trying to say. Your only error was in oversimplifying assumptions about the types of nicotinic receptors expressed by DA neurons, which, in addition to alpha7, definitely express significant quantities of alpha4beta2 on both cell bodies and axon terminals. The well-established nicotine-induced increases in striatal dopamine in vivocould not occur if the axon terminal effects I cite were not accompanied by the modulation of synaptic inputs, biasing the neurons toward phasic firing, that you cite.