Restoring volume control

Joined: 18 Dec 2008, 23:57

13 May 2006, 03:22 #11

Kenneth J. Kellar, Ph.D.
Department of Pharmacology
Georgetown University School of Medicine

What We Know

Nicotine's important effects on the brain, spinal cord, and autonomic nervous system are mediated by nicotinic cholinergic receptors. These receptors, which normally respond to the neurotransmitter acetylcholine, exist as several subtypes that differ in the details of their exact structure and characteristics, but each forms an ion channel through the cell membrane that allows sodium, potassium, and calcium ions to flow into or out of the cell when the receptor is activated by nicotine. This in turn typically leads to depolarization of the cell and an excitatory response. For example, nicotine stimulates cells in the adrenal gland to secrete epinephrine (adrenaline) into the blood, and thus it activates a number of systems collectively involved in the body's "fight or flight" responses.

Nicotinic receptors are found on neurons throughout the brain, including the cerebral cortex, thalamus, hypothalamus, hippocampus, basal ganglia, midbrain, and hindbrain. They are often associated with the cell bodies and axons of major neurotransmitter systems, and they appear to influence the release of several different neurotransmitters, including catecholamines, acetylcholine, GABA, and glutamate. Nicotine, in fact, stimulates the release of dopamine and norepinephrine in specific neuronal circuits thought to be closely involved in so-called reward functions. This action may underlie the addictive liability of nicotine; in fact, its action to stimulate dopamine neurotransmission in these specific reward circuits is consistent with the actions of other well-known drugs of abuse, such as cocaine and amphetamine.

In addition to its actions in the brain's reward circuits, nicotine stimulates the release of certain pituitary gland hormones, such as prolactin and ACTH. Measurement of nicotine's effects on these hormones offers a window on its in vivo pharmacological actions and can be used to assess how acute and chronic exposure to nicotine affect its receptors. For example, in rats a single injection of nicotine stimulates prolactin release, but a second injection given any time up to several hours after the first is ineffective, indicating that the nicotinic receptors are desensitized. This desensitization is reversible, and within about 12 hours after the first nicotine injection, receptor function is restored.

In contrast, after chronic exposure to nicotine (for 10 days), a single injection does not stimulate prolactin release even up to 8 days after chronic exposure has ended. This suggests that the function of these receptors is lost permanently - the receptors are inactivated as opposed to desensitized. Nicotine-stimulated prolactin release does return about 14 days after the last exposure to nicotine, time enough for new nicotinic receptors to be synthesized by the neurons involved. One of the interesting and more unusual aspects of nicotine's effects on brain nicotinic receptors is that chronic exposure to nicotine in rats, mice, and humans actually increases the density (number) of these receptors. Thus, in rats or mice exposed to nicotine for 7 to 21 days, the density of these receptors is increased by 30 to 100 percent in many areas of the brain. In the brains of smokers, the density of the nicotinic receptors is 100 to 300 percent higher than in nonsmokers. The higher density of receptors, however, may not necessarily translate into an increased level of functions mediated by these receptors. Quite the opposite may be the case, as demonstrated by the prolactin studies described above. On the other hand, recent studies that examined nicotine-stimulated dopamine and norepinephrine release in vivo found that administration of low doses of nicotine could actually increase the release of these neurotransmitters in some brain areas.

What We Need To Know More About

This difference in how chronic administration of nicotine affects nicotine-stimulated prolactin release and dopamine release in vivo probably reflects fundamental differences in the regulation of the subtypes of nicotinic receptors that mediate each of these responses. Thus, a critical task is to identify the receptor subtypes that are associated with the pharmacological actions of nicotine in altering neurotransmission and ultimately behavior. The means to accomplish this task are beginning to emerge in the form of new methods and tools to localize and identify the specific receptor subtypes in specific areas of the brain and spinal cord and in peripheral nervous tissue. These include new high-affinity ligands to label the receptors, subunit-specific antibodies that allow determination of the subunit composition of the receptor subtypes, patch-clamp measurements of the conductance, and rapid regulation of the receptors' ion channels. In addition, new approaches to studying the characteristics of the receptor subtypes and to determining their roles in vivo have been developed using the methods of recombinant molecular biology, including the production of stably transfected cell lines that express a single subtype of nicotinic receptor (which allows precise characterization of that receptor's properties) and knockout mice lacking a specific subunit of the receptors.

A fundamental question is, Which subtype(s) of nicotinic receptors are involved in the rewarding aspects of nicotine's actions? Is it the receptor that is inactivated by chronic nicotine and thus does not fully function after chronic exposure to nicotine? Is it the receptor whose function is actually increased during chronic exposure? Or is it a combination of receptor subtypes? And beyond the neurobiology of nicotine's actions on its receptors is an even more intriguing question: How do nicotine's effects on neurotransmission lead to alterations in the fundamental drives and behaviors associated with addiction? The means are available to begin to address these questions, and the answers are likely to have relevance to more than just nicotine addiction.

Recommended Reading

Benwell, E.M., and Balfour, D.J.K. Regional variation in the effects of nicotine on catecholamine overflow in rat brain. Eur J Pharmacol 325:13-20, 1997.

Hulihan-Giblin, B.A.; Lumpkin, M.D.; and Kellar, K.J. Acute effects of nicotine on prolactin release in the rat: Agonist and antagonist effects of a single injection of nicotine. J Pharmacol Exp Ther 252:15-20, 1990.

Hulihan-Giblin, B.A.; Lumpkin, M.D.; and Kellar, K.J. Effects of chronic administration of nicotine on prolactin release in the rat: Inactivation of prolactin release by repeated injections of nicotine. J Pharmacol Exp Ther 252:21-25, 1990.

Marshall, D.L.; Redfern, P.H.; and Wonnacott, S. Presynaptic nicotinic modulation of dopamine release in the three ascending pathways studied by in vivo microdialysis: Comparison of naive and chronic nicotine-treated rats. J Neurochem 68:1511-1519, 1997.

Wonnacott, S. Presynaptic nicotinic ACh receptors. Trends Neurosci 20:92-98, 1997.
Last edited by John (Gold) on 15 Feb 2009, 12:43, edited 1 time in total.

Joined: 19 Dec 2008, 01:50

12 Oct 2006, 22:09 #12

There is no way to avoid the down side. The pleasure pathways will not function at normal levels until the number of receptors on the affected nerve cells have time to readjust.

this is a brilliant post.

does anyone know how long the readjustment takes?

Joined: 18 Dec 2008, 23:57

13 Oct 2006, 02:38 #13

I had the same question myself, Squitz. I wrote the below response to another thread but it has equal application here. Still just one rule, Squitz ... no nicotine today, Never Take Another Puff! John

Animal studies suggest that different brain regions may re-sensitize or downregulate at different rates, some within a day but keep in mind that a rat's life expectancy is far shorter than a humans. This is the latest study -

Mugnaini M, Garzotti M, Sartori I, Pilla M, Repeto P, Heidbreder CA, Tessari M.

Excellent question, Sonya. I wish we had an single and consistent answer but science just isn't there yet. Everything I've read to date suggests that once nicotine's arrival stops resensitization commences in earnest and is completed rapidly in some brain regions, and with some types of acetylcholine receptors, while taking longer in others.

In my mind, correctly or incorrectly, I like to relate the brain's capacity to "downregulate" receptor counts to other physical healing such as restoration of our sense of smell or the healing of cilia in bronchial tubes (our sweeper brooms). But even after the initial healing of those functions, I'm sure there's additional gradual ongoing sensitivity restoration over time. The probem is that research in this area is ongoing , new, studies are hard to compare, and most studies are of mice or rats, although we do a couple on humans.

New studies continue to come out and tend to openly declare how little we currently know in making statements such as "chronic nicotine exposure induces upregulation of nicotinic receptors, but the mechanisms underlying this phenomenon are not well understood" (see
Nuutinen S, Ekokoski E, Lahdensuo E, Tuominen RK. ). Downregulation has been studied even less.
Last edited by John (Gold) on 15 Feb 2009, 12:47, edited 1 time in total.

Joined: 19 Dec 2008, 00:02

11 Jan 2007, 08:54 #14

"Over time, receptor numbers, their sensitivity, and patterns of release of neurotransmitters all revert to normal, once again producing normal levels of signalling along the pathways."

That is good news! Thanks for this article link, Sal.


Joined: 18 Dec 2008, 23:57

17 May 2007, 21:16 #15

From above:
So 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 along the many affected pathways will change to levels far from normal.

If the drug is not reintroduced, the altered level of signalling will eventually induce 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 signalling along the pathways.

There is no way to avoid the down side. The pleasure pathways will not function at normal levels until the number of receptors on the affected nerve cells have time to readjust.
Adjustment to re-sensitization
Coming to terms with years of denial rationalizations,
Yep! Just one hour, challenge and day at a time recovery is doable

Joined: 18 Dec 2008, 23:57

29 Jun 2007, 04:38 #16

Slavery's Onset
Last edited by John (Gold) on 26 Mar 2009, 20:09, edited 1 time in total.

Joined: 16 Jan 2003, 08:00

13 Aug 2007, 06:49 #17

Comfort will arrive no matter how much you smoked or how long you smoked. Your brain needs to heal and as long as nicotine is not reintroduced it will happen.

So many of us never knew that we would not spend the rest of our lives wanting or craving nicotine! It starts with an hour, and then hours, and then a whole day, and then days, and weeks, and then months and then YEARS.

Let yourself heal. Cultivate Patience .

No nicotine today, one day at a time. Never take another puff.

Last edited by Sal GOLD.ffn on 27 Aug 2009, 17:21, edited 1 time in total.

Joined: 19 Dec 2008, 00:00

02 Mar 2008, 04:16 #18

Very informative. I am still learning so much.

Joined: 11 Nov 2008, 19:22

16 Jun 2009, 17:00 #19

Drug addiction is about an external chemical fooling the brain into believing that that next fix is as important as eating. Whipped by insula driven urges, craves and anxieties, rewarded by dopamine flow during nicotine use anticipation or its actual arrival, the brain's species survival event pay-attention pathways are functioning as designed. Food craves, nicotine craves, food "aaah" sensations, nicotine "aaah"s. The only problem is that without nicotine our species thrives and without food, water or reproduction it dies. Yes, drug addiction is about living a lie. There's just one rule that if followed allows us to see the light and reveal the lie ... no nicotine today!

Breathe deep, hug hard, live long,

John (Gold x10)

Joined: 06 Dec 2008, 16:58

27 Aug 2009, 17:26 #20


Joined: 14 Nov 2010, 15:34

17 Nov 2010, 20:02 #21

This is such an interesting post....Thank you. I wondered why i feel sad more often than i did. At least I now know why and also know that things will get better. After 9 days nicotene free and with the support of why quit, joels videos and reading all these posts I have the most strength I've had in years. I'm very angry at the tobacco industry full stop and angry at the NHS for pushing all these NRT products. I went to one of there groups last week thinking they might be able to support me more in person. Out of the 20-30 people there I was the only one quitting cold turkey and 90% of them looked terrified.... I told them about this site but the people doing the clinic were so in favour of NRT... such a shame. The one or two who were doing o.k would have done even better if they had quit cold turkey. All of them seemed like they were still desperate to smoke. I found it really quite sad - I wanted to bring them all home and show them what I'd found on here.
Thank you all so much X