A biochemical model of nicotine dependency

Joined: November 11th, 2008, 7:22 pm

December 22nd, 2009, 3:27 pm #1

A biochemical model
of nicotine dependency
Brain cells communicate with each other by way of chemicals called neurotransmitters, that are released from one cell and attach to nearby receptors on another brain cell, causing what researchers term, activation, modulation or stimulation of the bran cell. But what happens when an external chemical like nicotine enters the brain and by happenstance is so similar to a natural neurotransmitter that it is able to dock at receptors and directly activate adjoining brain cells?

Before going further, don't get thrown by the term "nicotinic" receptors. Even never-smokers have nicotinic receptors. In fact, it's the mind's most abundant type of acetylcholine receptor. It got its name, not because it occurs only in nicotine addicts but because its discovery was related to the fact that nicotine was found to activate it.

Researchers have long known that nicotine attaches to nicotinic-type acetylcholine receptors (abbreviated nAChRs), the primary path responsible for hijacking and enslaving brain dopamine pathways. Factually, they also knew that while nicotine stimulates the flow of dopamine, it both desensitizes nicotinic receptors and causes the brain to grow or activate millions of extra receptors in multiple brain regions, a process known as upregulation. But until now theories that tried to piece together the nicotine dependency puzzle haven't fit together well at all.

Researchers remained baffled. If the brain desensitizes nicotinic receptors as to nicotine's presence, then why go in the opposite direction by upregulating and increasing the number of nicotinic receptors? Existing explanations also failed to explain nicotine dependency, as upregulation, with more nicotinic receptors, would seem to imply less need for nicotine not more.

Now, Professors Marcelo O. Ortells and Georgina E. Barrantes of Argentina's University of Morón offer the most cohesive explanation yet in a December 2009 Medical Hypotheses article entitled "Tobacco Addiction: A biochemical model of nicotine dependence." While much of their 11 page paper is written in language that I'm sure the average molecular biologists can easily decipher, it's way over my head. Even so, what I'm able to glean fits snuggly with my own dependency history, its onset, increases in level of tolerance (needing to smoke more over the years), relapse and why these professors cannot explain how using replacement nicotine (NRT) allows the brain to adjust to functioning without it.

According to Professors Ortells and Barrantes, "Three main processes have been related to tobacco addiction: nAChR modulation of the dopaminergic and glutamatergic systems, nAChR upregulation by nicotine and nAChR desensitization by nicotine."

In a nutshell, Professors Ortells and Barrantes hypothize that repeated use of nicotine desensitizes nicotinic receptors, causing the brain to increase or upregulate the number of receptors. While receptor desensitization to nicotine distrupts dopamine flow (providing negative feedback), nAChR upregulation is the reinforcing process of nicotine dependence. It actually wires the human brain to function on nicotine's presence and any attempt to stop using it compels the nicotine dependent mind to have to wait for resensitization and downregulation before feeling normal again.

Below is a copy of the study's summary (abstract), followed by a few select quotes from the study's full text. This paper provides reasoning for what each of us have already lived. To stay on this side of the bars and keep our now arrested dependency on the other requires adherence to one guiding principle ... no nicotine today!

Breathe deep, hug hard, live long,

John (Gold x10)

Med Hypotheses. 2009 Dec 2. [Epub ahead of print]

Tobacco addiction: A biochemical model of nicotine dependence. Ortells MO, Barrantes GE.

Facultad de Medicina, Universidad de Morón - Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.

Nicotine is the main psychoactive substance present in tobacco, targeting in the CNS the nicotinic acetylcholine receptors (nAChR). The main effects of nicotine associated with smoking are nAChR upregulation, nAChR desensitization and modulation of the dopaminergic system. However, there is a lack of a comprehensive explanation of their roles that effectively makes clear how nicotine dependence might be established on those grounds. Receptor upregulation is an unusual effect for a drug of abuse, because theoretically this implies less need for drug consumption. Receptor upregulation and receptor desensitization are commonly viewed as opposite, homeostatic mechanisms.

We here analyze the available information under a model in which both receptor upregulation and receptor desensitization are responsible for establishing a mechanism of nicotine dependence, consequently having an important role in starting and maintaining tobacco addiction.

We propose that negative feedbacks on dopamine release regulated by alpha4beta2 nAChRs are disrupted by nicotine. nAChR desensitization is the disrupting mechanism, while nAChR upregulation is the reinforcing process of nicotine dependence, which eventually initiates tobacco addiction. A conclusion of the model is that drugs used for smoking cessation should inhibit preferentially alpha4beta2 nAChRs and to have a low or null ability to upregulate nAChRs, as this characteristic allows the smoker to achieve downregulation without abstinence symptoms. A relationship between this hypothesis and smoking and schizophrenia is also discussed.

PMID: 19962246 [PubMed - as supplied by publisher]

PubMed Source Link

Select Study Quotes

Physiological roles of desensitization and upregulation in tobacco addiction. Because nicotine promotes both, upregulation and desensitization are thought to be central to nicotine addiction. Desensitization is an intrinsic feature of the molecular structure of nAChRs [20] and nicotine is highly effective in promoting it, especially in the a4b2 receptor. Upregulation on the other hand, has only been observed after external administration of agonists, especially nicotine.

Upregulation by nicotine is at first view paradoxical [23], because the number of receptors is increased in a sort of positive feedback, contrary to what is normally expected for a drug of abuse. One possible explanation is that this increment is a homeostatic response to desensitization [16,24]. In contrast, others have proposed that desensitization might represent a cellular basis of nicotine tolerance [5]
, especially in the presence of upregulation.

The described explanations for upregulation (homeostatic response to desensitization) and desensitization (a mechanism for nicotine tolerance) make emphasis on their independent roles as putative corrective mechanisms, but they have no direct relationship with a mechanism of nicotine dependence. Furthermore, they are not compatible because only one can represent a problem that the brain must compensate. If nicotine activation of nAChRs is a problem and needs to be balanced by desensitization, then upregulation, going in the opposite direction, should not be needed. However, if desensitization is the main disruptive process, then upregulation does make sense as a way to compensate the lost signaling capability. However, none of these scenarios explains how nicotine dependence is initiated.

Hypothesis II: nicotine inactivation of nAChRs as the basis of nicotine dependence. As a second scenario, we assume that it is nAChR inactivation by nicotine desensitization, what initiates the dependence mechanism and eventually addiction. In this case nAChR inactivation enhances release, for example, through the desensitization of nAChRs present on inhibitory GABAergic neurons (see below). A logical consequence is that the upregulation that follows desensitization completes the mechanism of nicotine dependence. In effect, independently of the mechanisms triggered by nAChR desensitization to enhance DA release (see below), upregulation makes more difficult to achieve inactivation (and rewarding). Consequently, upregulation promotes the need of higher or faster nicotine consumption. Therefore, in this hypothesis nicotine provokes both the rewarding stimulus (via desensitization) and the need for more nicotine consumption (via upregulation).
Last edited by JohnPolito on December 22nd, 2009, 3:36 pm, edited 1 time in total.