Nicotine - a neuromodulator

John (Gold)
John (Gold)

12:22 AM - Oct 24, 2003 #1

Smoking and Drug Addiction
by Dr. George Johnson - Backgrounders
The body sometimes deliberately prolongs the transmission of a signal across a synapse by slowing the destruction of neurotransmitters. It does this by releasing into the synapse special long-lasting chemicals called neuromodulators. Some neuromodulators aid the release of neurotransmitters into the synapse; others inhibit the reabsorption of neurotransmitters so that they remain in the synapse; still others delay the breakdown of neurotransmitters after their reabsorption, leaving them in the tip to be released back into the synapse when the next signal arrives.
Mood, pleasure, pain, and other mental states are determined by particular groups of neurons in the brain that use special sets of neurotransmitters and neuromodulators. Mood, for example, is strongly influenced by the neurotransmitter serotonin. Many researchers think that depression results from a shortage of serotonin. Prozac, the world's bestselling antidepressant, inhibits the reabsorption of serotonin, thus increasing the amount in the synapse (figure 4).
Figure 4 Drugs alter transmission of impulses across the synapse.
Depression can result from a shortage of the neurotransmitter serotonin. The antidepressant drug Prozac works by blocking reabsorption of serotonin in the synapse, making up for the shortage.
Drug Addiction
When a cell of the body is exposed to a chemical signal for a prolonged period, it tends to lose its ability to respond to the stimulus with its original intensity. (You are familiar with this loss of sensitivity-when you sit in a chair, how long are you aware of the chair?) Nerve cells are particularly prone to this loss of sensitivity. If receptor proteins within synapses are exposed to high levels of neurotransmitter molecules for prolonged periods, that nerve cell often responds by inserting fewer receptor proteins into the membrane. This feedback is a normal part of the functioning of all neurons, a simple mechanism that has evolved to make the cell more efficient by adjusting the number of "tools" (receptor proteins) in the membrane "workshop" to suit the workload.
Cocaine. The drug cocaine is a neuromodulator that causes abnormally large amounts of neurotransmitters to remain in the synapses for long periods of time. Cocaine affects nerve cells in the brain's pleasure pathways (the so-called limbic system). These cells transmit pleasure messages using the neurotransmitter dopamine. Using radioactively labeled cocaine molecules, investigators found that cocaine binds tightly to the transporter proteins in the gaps between nerves. These proteins normally remove the neurotransmitter dopamine after it has acted. Like a game of musical chairs in which all the chairs become occupied, there are no unoccupied carrier proteins available to the dopamine molecules, so the dopamine stays in the gap, firing the receptors again and again. As new signals arrive, more and more dopamine is added, firing the pleasure pathway more and more often.
When receptor proteins on limbic system nerve cells are exposed to high levels of dopamine neurotransmitter molecules for prolonged periods of time, the nerve cells "turn down the volume" of the signal by lowering the number of receptor proteins on their surfaces. They respond to the greater number of neurotransmitter molecules by simply reducing the number of targets available for these molecules to hit. The cocaine user is now addicted (figure 5). Addiction occurs when chronic exposure to a drug induces the nervous system to adapt physiologically. With so few receptors, the user needs the drug to maintain even normal levels of limbic activity.
Is Addiction to Smoking Cigarettes Drug Addiction?
Investigators attempting to explore the habit-forming nature of smoking cigarettes used what had been learned about cocaine to carry out what seems a reasonable experiment-they introduced radioactively labeled nicotine from tobacco into the brain and looked to see what sort of carrier protein it attached itself to. To their great surprise, the nicotine ignored proteins in the between-cell gaps and instead bound directly to a specific receptor on the receiving nerve cell surface! This was totally unexpected, as nicotine does not normally occur in the brain-why should it have a receptor there?
Intensive research followed, and researchers soon learned that the "nicotine receptors" normally served to bind the neurotransmitter acetylcholine. It was just an accident of nature that nicotine, an obscure chemical from a tobacco plant, was also able to bind to them. What, then, is the normal function of these receptors? The target of considerable research, these receptors turned out to be one of the brain's most important tools. The brain uses them to coordinate the activities of many other kinds of receptors, acting to "fine-tune" the sensitivity of a wide variety of behaviors.
When neurobiologists compare the limbic system nerve cells of smokers to those of nonsmokers, they find changes in both the number of nicotine receptors and in the levels of RNA used to make the receptors. They have found that the brain adjusts to prolonged exposure to nicotine by "turning down the volume" in two ways: (1) by making fewer receptor proteins to which nicotine can bind; and (2) by altering the pattern of activation of the nicotine receptors (that is, their sensitivity to neurotransmitters).
It is this second adjustment that is responsible for the profound effect smoking has on the brain's activities. By overriding the normal system used by the brain to coordinate its many activities, nicotine alters the pattern of release into gaps between nerve cells of many neurotransmitters, including acetylcholine, dopamine, serotonin, and many others. As a result, changes in level of activity occur in a wide variety of nerve pathways within the brain.
Addiction to nicotine occurs because the brain compensates for the many changes nicotine induces by making other changes. Adjustments are made to the numbers and sensitivities of many kinds of receptors within the brain, restoring an appropriate balance of activity.
Now what happens if you stop smoking? Everything is out of whack! The newly coordinated system requires nicotine to achieve an appropriate balance of nerve pathway activities. This is addiction in any sensible use of the term. The body's physiological response is profound and unavoidable. There is no way to prevent addiction to nicotine with willpower, any more than willpower can stop a bullet when playing Russian roulette with a loaded gun. If you smoke cigarettes for a prolonged period, you will become addicted.
What do you do if you are addicted to smoking cigarettes and you want to stop? When use of an addictive drug like nicotine is stopped, the level of signaling changes to levels far from normal. If the drug is not reintroduced, the altered level of signaling eventually induces the nerve cells to once again make compensatory changes that restore an appropriate balance of activities within the brain. Over time, receptor numbers, their sensitivity, and patterns of release of neurotransmitters all revert to normal, once again producing normal levels of signaling along the pathways. There is no way to avoid the down side of addiction. The pleasure pathways will not function at normal levels until the number of receptors on the affected nerve cells has time to readjust.
Many people attempt to quit smoking by using patches containing nicotine; the idea is that by providing gradually smaller doses of nicotine, the smoker can be weaned of his or her craving for cigarettes. The patches do reduce the craving for cigarettes-as long as you keep using the patches! Actually, using such patches simply substitutes one (admittedly less dangerous) nicotine source for another. If you are going to quit smoking, there is no way to avoid the necessity of eliminating the drug to which you are addicted. Hard as it is to hear the bad news, there is no easy way out. The only way to quit is to quit.
Cigarette smokers find it difficult to quit because they have become addicted to nicotine, a powerful neuromodulator.
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Last edited by John (Gold) on 6:40 PM - Feb 07, 2009, edited 1 time in total.

Debaria Silver1
Debaria Silver1

4:36 AM - Oct 24, 2003 #2

Very powerful stuff in helping one understand the mental processes that go on with breaking addiction. Thanks, every bit of education I can get my hands on helps.

3 Weeks, 15 hours free from nicotine. 432 not smoked, $86.40 saved!!!


9:51 AM - Oct 24, 2003 #3

Thank-you, John for another fascinating and informative post.i just love all the neurobiology stuff !


2:01 PM - Oct 24, 2003 #4

Thanks John. That was some very interesting info.
Free of cigarettes for 3 weeks and 2 days.


11:23 PM - Oct 24, 2003 #5

Fascinating read, John! Thanks for keeping us educated!


John (Gold)
John (Gold)

12:21 AM - Oct 25, 2003 #6

After posting Dr. Johnson's excellent description of nicotine dependency I realized that it was page #2 of his two part explanation, with page #1 being a more basic intro to understanding how normal neurotransmitters function. Sorry about that. This is the link to page #1.
I also want to mention that while visiting science and the lowest levels of cutting edge dependency understanding can be enlightening, as has been proven by the the almost one billion comfortable ex-smokers who became free without such detailed insights, the only rule we must each follow in order to stay on this side of acceptance is to Never Take Another Puff!
Last edited by John (Gold) on 6:46 PM - Feb 07, 2009, edited 2 times in total.

John (Gold)
John (Gold)

11:17 AM - Feb 08, 2004 #7

Although the core principles taught here at Freedom reflect a 100% full-proof method of avoiding relapse (no nicotine just one day at a time, never take another puff), with each passing month science discovers greater detail about how nicotine operates inside the human mind and body. Below is a quick sampling of their latest study finding, all published in 2004.

Clearly we don't need to know or understand any of the below scientific mumbo jumbo in order to reclaim and maintain control of our mind, health and life but it hopefully gives you a brief glimpse of just how deep our addiction and nicotine go. I've highlighted in blue the portion of each study that seems almost understandable.

As you look at them keep in mind that nicotine not only imitates the important neurochemical acetylcholine, the receptors designed to receive and recognize acetylcholine are at least twice as attracted to the nicotine molecule. If we have any biology majors out there who want to break these studies down into layman's terms we're all ears

J Biol Chem. 2004 Feb 5

An extracellular microdomain controls up-regulation of neuronal nicotinic acetylcholine receptors by nicotine.

Sallette J, Bohler S, Benoit P, Soudant M, Pons S, Le Novere N, Changeux JP, Corringer PJ.

Rcepteurs Cognition, Institut Pasteur, PARIS 75728 Cedex 15.

In smokers brain, rodent brain, and in cultured cells expressing nicotinic receptors, chronic nicotine treatment induces an increase in the total number of high-affinity receptors for acetylcholine and nicotine, a process referred to as up-regulation. Up-regulation induced by 1 mM nicotine reaches 6-fold for alpha3beta2 nicotinic receptors transiently expressed in HEK293 cells, whereas it is much smaller for alpha3beta4 receptors, offering a rationale to investigate the molecular mechanism underlying up-regulation. In this expression system, binding sites are mainly intracellular, as shown by [(3)H]-epibatidine binding experiments, and competition with the impermeant ligand carbamylcholine. Systematic analysis of beta2/beta4 chimeras demonstrates that: (i) the extracellular domain critically contributes to up-regulation; (ii) only residues belonging to two beta2 segments, 74-89 and 106-115 confer up-regulation to beta4, mainly by decreasing the amount of binding sites in the absence of nicotine: on an atomic 3D model of the alpha3beta2 receptor, these amino acids form a compact microdomain which mainly contributes to the subunit interface, and also faces the acetylcholine binding site; (iii) the beta4 microdomain is sufficient to confer to beta2 a beta4-like up-regulation, (iv) this microdomain makes an equivalent contribution to the up-regulation differences between alpha4beta2 and alpha4beta4. We propose that nicotine, by binding to immature oligomers, elicits a conformational reorganization of the microdomain, strengthening the interaction between adjacent subunits and thus facilitating maturation processes toward high affinity receptors. This mechanism may be central to nicotine addiction, since alpha4beta2 is the subtype exhibiting the highest degree of up-regulation in the brain.

PMID: 14764595 [PubMed - as supplied by publisher]

Carcinogenesis. 2004 Feb 4

Cytokine production by alveolar macrophages is down regulated by the {alpha}-methylhydroxylation pathway of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

Proulx LI, Castonguay A, Bissonnette EY.

Centre de Recherche, Hopital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Universite Laval.

NNK, a nicotine derived nitrosamine, is a potent lung carcinogen that generates electrophilic intermediates capable of damaging DNA. The effects of NNK on the immune response, which may facilitate lung carcinogenesis, are poorly understood. Alveolar macrophages (AM), a key cell in the maintenance of lung homeostasis, metabolize NNK via two major metabolic activation pathways: alpha-methylhydroxylation and alpha-methylenehydroxylation. We have previously shown that NNK inhibits the production of interleukin-12 (IL-12) and tumor necrosis factor (TNF), but stimulates the production of IL-10 and prostaglandin E2 (PGE2) by AM. In the present study, we investigated the contribution of each activation pathway in the modulation of AM function. We used two precursors, 4-[(acetoxymethyl)-nitrosamino]-1-(3-pyridyl)-1-butanone (NNKOAc) and N-nitro(acetoxymethyl)methylamine (NDMAOAc), which generate the reactive electrophilic intermediates (4-(3-pyridyl)-4-oxo-butanediazohydroxyde and methanediazohydroxyde, respectively) in high yield and exclusively. Rat AM cell line, NR8383, was stimulated and treated with different concentrations of NNKOAc or NDMAOAc (12, 25, and 50 micro M). Mediator release was measured in cell-free supernatants. NNKOAc significantly inhibited the production of IL-10, IL-12, TNF, and NO but increased the release of PGE2 and COX-2 expression suggesting that the alpha-methylhydroxylation pathway might be responsible for NNK modulation of AM cytokine release. In contrast, NDMAOAc did not modulate AM mediator production. However, none of these precursors, alone or in combination, could explain the stimulation of AM IL-10 production by NNK. Our results suggest that the alphamethylhydroxylation of NNK leading to DNA pyridyloxobutylation also modulates cytokine production in NNK-treated AM.

PMID: 14764458
Int J Neurosci. 2004;114(3):381-390.


Ascioglu M, Dolu N, Golgeli A, Suer C, Ozesmi C.

Erciyes University, Medical Faculty, Department of Physiology, Kayseri, Turkey.

Several previous studies have reported that cigarette smoking enhances performance of cognitive processing. These enhancements are generally attributed to the pharmacological effects of nicotine, while there is some debate whether the effects of smoking/nicotine are a result of recovery from abstinence. Evoked potentials (EPs) and event related potentials (ERPs) of the brain have been applied as an index of information processing in a wide variety of normal and cognitive impaired subjects. This study was carried out on 20 healthy students (23 2.3 years old) from the medical faculty of City University. Study population comprised ten chronic cigarette smokers consuming an average of 14 4.2 cigarettes per day, with a history of smoking for more than one year. Ten non -smokers served as control. Standard oddball paradigm was presented, and EEG activity was recorded at the Fz, Cz, Pz electrode sites. Twenty responses to target stimuli were averaged at each location. N1, P2, N2, and P300 components were evaluated in these recordings. Amplitudes were measured relative to prestimulus baseline, and peak latencies were defined as the time point of maximum amplitude. It was found that there were no significant differences between either N1, P2, N2, P300 amplitudes or peak latency values of cigarette smokers and non smokers. As a result, chronic cigarette smoking generally does not improve cognitive processing.

PMID: 14754662
Prog Neuropsychopharmacol Biol Psychiatry. 2004 Mar;28(2):319-27. language=JavaScript1.2>

Regional cerebral blood flow and plasma nicotine after smoking tobacco cigarettes.

Domino EF, Ni L, Xu Y, Koeppe RA, Guthrie S, Zubieta JK.

Department of Pharmacology, University of Michigan, Box 0632, MI 48109-0632, Ann Arbor, USA

The hypothesis for this research is that only in some brain areas, regional cerebral blood flow (rCBF) after tobacco smoking is correlated with arterial plasma nicotine concentrations. Twenty-one healthy adult tobacco smokers of both genders were studied after overnight tobacco abstinence. H(2)15O water was used to measure rCBF. Six separate scans were taken about 12 min apart with the subjects' eyes closed and relaxed. Research tobacco cigarettes smoked were of average (1.0 mg) and low (0.08 mg) nicotine but similar tar yield (9.5 and 9.1 mg). Increases in normalized rCBF were obtained in the occipital cortex, cerebellum, and thalamus, and decreases in the anterior cingulate, nucleus accumbens, amygdala, and hippocampus immediately after smoking the first average nicotine yield cigarette of the morning. After smoking the second average nicotine yield cigarette, the effects were less than smoking the first. Low-nicotine cigarettes produced fewer changes in rCBF than those after the first average cigarette. As expected, statistically significant correlations were found between increases in arterial plasma nicotine and HR. Correlations with arterial nicotine on rCBF were statistically significant in brain areas with the greatest changes in relative blood flow such as the cerebellum and occipital cortex. Nicotine delivery by tobacco smoking is only one of the factors, which contribute to changes in rCBF.

PMID: 14751429

Endocrinology. 2004 Feb 5 language=JavaScript1.2>

Acetylcholine Is an Autocrine or Paracrine Hormone Synthesized and Secreted by Airway Bronchial Epithelial Cells.

Proskocil BJ, Sekhon HS, Jia Y, Savchenko V, Blakely RD, Lindstrom J, Spindel ER.

Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, 97006; Department of Pathology, Oregon Health & Science University, Portland, OR, 97201; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232; Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104.

The role of acetylcholine (ACh) as a key neurotransmitter in the central and peripheral nervous system is well established. However the role of ACh may be broader in that ACh may also function as an autocrine or paracrine signaling molecule in a variety of non-neuronal tissues. To begin to establish ACh of non-neuronal origin as a paracrine hormone in lung, we have examined neonatal and adult monkey bronchial epithelium for the components involved in nicotinic cholinergic signaling. Using immunohistochemistry and reverse transcriptase PCR, we have demonstrated in lung bronchial epithelial cells expression of choline acetyltransferase (ChAT), the vesicular acetylcholine transporter (VAChT), the choline high affinity transporter (CHT), alpha7, alpha4 and beta2 nicotinic ACh receptor (nAChR) subunits, and the nAChR accessory protein lynx1. Confocal microscopy demonstrates that these factors are expressed in epithelial cells and are clearly distinct from neighboring nerve fibers. Confirmation of RNA identity has been confirmed by partial sequence analysis of PCR products and by cDNA cloning. Primary culture of bronchial epithelial cells confirms the synthesis and secretion of ACh and the activity of cholinesterases. Thus ACh meets all the criteria for an autocrine/paracrine hormone in lung bronchial epithelium. The non-neuronal cholinergic signaling pathway in lung provides a potentially important target for cholinergic drugs. This pathway may also explain some of the effects of nicotine on fetal development and also provides additional mechanisms by which smoking effects lung cancer growth and development.

PMID: 14764638 [PubMed - as supplied by publisher]

JoeJFree Gold
JoeJFree Gold

1:07 AM - Feb 09, 2007 #8

Here are links to several articles found in the Topic Index that can help to develop an understanding of and appreciation for the relative effect of nicotine in comparison to other chemical compounds that foster true chemical addiction dependence.

Still as John says in the preface to his post #9 above:
Although the core principles taught here at Freedom reflect a 100% full-proof method of avoiding relapse (no nicotine just one day at a time, never take another puff), with each passing month science discovers greater detail about how nicotine operates inside the human mind and body. Below is a quick sampling of their latest study finding, all published in 2004.

Clearly we don't need to know or understand any of the below scientific mumbo jumbo in order to reclaim and maintain control of our mind, health and life but it hopefully gives you a brief glimpse of just how deep our addiction and nicotine go.
Read more here:  Nicotine
Last edited by JoeJFree Gold on 3:50 PM - Jun 12, 2013, edited 1 time in total.