Tuesday, April 17, 2007

Got nicotine?

As a pledge-signing member of my elementary school's rigorous D.A.R.E. program, I was regularly exposed to horrific photographs of blackened lungs and deteriorating hearts, and was utterly convinced that cigarettes ravaged and destroyed everything they touched. Thus when my dad started smoking when I was about 5, I (with my mom's encouragement) flushed pack after pack down the toilet until he quit. I still do not smoke, and I don't plan to, but I have grown a bit more discerning with respect to sensationalist demonization of various pleasure-enhancing drugs.

It turns out that of the 4,000 or so compounds in tobacco smoke, including a variety of carcinogens, and toxins such as carbon monoxide, heavy metals, and cyanide, at least one ingredient actually has some beneficial effects: nicotine. There is a large body of research showing that nicotine, the ingredient that drives people to addiction, improves cognitive function in humans and laboratory animals. The most robust effect demonstrated in human smokers is an enhanced ability to sustain attention to a task for a prolonged period of time, an ability inextricably linked to learning and memory. Of course, learning and memory involve a number of processes (acquisition, encoding, storage, and retrieval), but the ability to concentrate on particular stimuli and screen out the rest is critical for the success of this operation.

Nicotine's beneficial effects on these "higher" cognitive functions have prompted efforts to develop nicotinic treatments for diseases associated with cognitive impairment, such as Alzheimer's disease, Parkinson's disease, attention deficit/hyperactivity disorder, and schizophrenia. However, this area of drug development is impeded by the complexity of nicotine's actions, including the observation that cognitive improvements have only been reliably detected in either smokers or the cognitively impaired. In contrast, nicotine tends to have deleterious effects on cognitive performance in "normal" non-smokers. (Another factor hampering the development of nicotine-based therapies is that they offer pharmaceutical companies little potential for financial gain, as nicotine sources are easy to come by.)

So how does nicotine affect cognitive function? First, a bit about how neurons communicate with each other. Some people may be able to skip the next few paragraphs (which I've distinguished with altered formatting), but I've included them anyways because it's important to have at least a rough idea of this process in order to understand how nicotine works in our brains.
Neurons are functionally integrated in expansive neural networks, with each neuron receiving up to thousands of inputs from other neurons. However, the vast majority of neurons* are not actually physically connected to one another; there is a tiny gap that separates neurons, called a synapse.

When a neuron is activated, an electrical pulse (an action potential) travels down its membrane; the neuron is said to "fire" an action potential. When the action potential reaches the end of the neuron, it cannot traverse the synapse, but instead induces the release of chemicals which can. Once liberated from the "pre-synaptic" neuron, these chemicals (called neurotransmitters) navigate across the synapse and bind to specific receptors on the "post-synaptic" neuron. Once bound, the neurotransmitters induce one of many physiological changes: they can make it easier to fire an action potential ("excitatory" neurotrasmitters), more difficult to fire an action potential ("inhibitory" neurotransmitters), or modulate the firing rate or other behavioral properties of the cell.

An overwhelming number of pre-synaptic neurons, all of which are sources of neurotransmitters, impinge on a single post-synaptic neuron, yet the latter responds with a binary decision: fire or don't fire. The cell creates order from this chemical deluge by performing a complex, time-dependent summation of all of its inputs; if it receives a sufficient number of excitatory inputs within a reasonable time window, it will fire an action potential and release its own neurotransmitter, passing the information along the circuit.
Each neurotransmitter can bind to a number of complementary receptors. One of the receptors for a neurotransmitter called acetylcholine (ACh) happens to also bind and respond to nicotine, which is not naturally present in the body. Thus when a post-synaptic neuron containing these particular receptors (called nicotinic ACh receptors, or nAChRs) is exposed to nicotine (as in when someone smokes a cigarette), it behaves as if it has been influenced by ACh; i.e. to an individual nAChR, nicotine and ACh are indistinguishable.
However, there is a crucial difference at the circuit level: ACh is regulated by your body, so it is typically released in small amounts by specific subsets of neurons at any given time. In contrast, nicotine, entering your body from an external source, can potentially act at all nAChR-bearing neurons simultaneously, leading to widespread activation and an assortment of consequences (including the release of other neurotransmitters, such as dopamine, endorphins, and ACh itself).

Turns out that the prefrontal cortex (PFC), a brain structure with a critical role in learning and memory, contains an abundance of nAChRs. This area receives information from all of the senses, and aids the learning process by directing attention to a limited set of input streams at a time. Like many cortical synapses, the excitatory synapses in the PFC are plastic, capable of undergoing systematic changes in synaptic strength/efficacy.

These changes are thought to underlie the processing and storage of information in neural circuits, and for that reason take place in a functionally relevant manner (i.e. one that is dependent on the activity of that particular synapse). Specifically, the robustness and direction (stronger or weaker) of the change in synaptic strength is dependent on the precise timing of pre-synaptic inputs and post-synaptic action potentials (also called "spikes"). This temporal correlation gives the process its name: spike-timing-dependent plasticity (STDP). According to the rules of STDP, a synapse with a high temporal correlation between pre-and post-synaptic activity will strengthen.

Importantly, excitatory synapses in the PFC change during working-memory related tasks, implicating the PFC in these cognitive behaviors. It is likely that nicotine's effects on attention and working memory are effectuated at the nAChR-containing synapses of the PFC, but the mechanistic changes are unknown. Moreover, it is unclear how these synaptic changes affect the functional properties of the circuit underlying these cognitive processes.

A group from Amsterdam, led by Huibert Mansvelder, published a study that explored the cellular and synaptic mechanisms of nicotine's actions in the most recent issue of Neuron, with a focus on how nicotine affects STDP in the PFC.

The scientists cut rat PFCs into slices, and induced STDP by electrically stimulating pre- and corresponding post-synaptic cells simultaneously. After repeating this paired stimulation (50 times), the synapse becomes "potentiated," meaning the pre-synaptic neuron becomes more effective at stimulating the same post-synaptic cell than it was before the procedure; i.e. the synapse is "stronger".

When nicotine was applied to the solution bathing the slice, this potentiation failed to occur. The blockade of STDP could be overcome, however, by increasing the electrical activity of the post-synaptic cell, indicating that the pairing procedure was less effective, but not defunct. The group found that nicotine's net effect was to enhance the release of a major inhibitory neurotransmitter, called GABA. In the context of the synapse, the post-synaptic neuron would thus be bombarded by copious amounts of GABA, which would then dominate the input summation. These actions decrease the likelihood that the post-synaptic neuron will fire, thereby interfering with the concomitant activation of both synaptic partners and interfering with STDP.

So how does impeding STDP, a process thought to provide the cellular foundation for an adaptive nervous system, enhance cognitive function in certain individuals? This question brings us back to attention--the ability to concentrate on relevant stimuli while ignoring that which is irrelevant. During PFC-based cognitive behaviors, the neural activity in the PFC may increase to distracting levels. By enhancing inhibitory neurotransmission, nicotine may enhance the "signal-to-noise" ratio, thereby improving attention selectivity. This may be particularly beneficial to smokers who are accustomed to high nicotinic stimulation, as well as individuals with cognitive impairment, as both these groups are functioning suboptimally in the absence of nicotine.

And what about normal individuals, whose cognitive functioning is often impaired with nicotine? Such "drug-free" individuals are probably already performing at or near their optimal level of performance. As a result, increasing nicotinic stimulation and interfering with STDP will have negative effects in most situations. It is possible, however, that even in "normal" individuals, nicotine may enhance cognitive function under extreme task demands. During such tasks, which necessitate intensified attention over a prolonged period of time, optimal performance may be facilitated by nicotinic stimulation.



*My explanation of synaptic transmission describes, specifically, a chemical synapse. These are the predominant form of synapses in the brain, but neurons can also be connected by channels called "gap junctions." The openings of these channels allow ions to flow from one neuron to the next, enabling electrical signals to pass directly between neurons. This type of connection is called an electrical synapse, and the transmission of information is much more rapid than at chemical synapses.

60 comments:

admin said...

Thank you, Madam, for detailed information. Much appreciated! It would be great if you could further attribute the psychological aspects of the smoking life-cycle: starting-handing-quitting.

Best , Mil > I quit, indeed!

yellodog said...

Came by way of Cognitive Daily and want to thank you for the thoughtful piece.
I'm currently planning to quit smoking for the 782nd time, and this problem (i.e., increased stupidity without nicotine) has always been a stumbling block. The cost/benefit has always been a little out of whack for me because I wonder why I should want a longer, stupid life more than a shorter, smarter one.
Is there a drug other than nicotine that performs this way? And is oral/patch ingested nicotine acting with the same 'nicotine cloud' effect, because that has not been my personal experience with nicotine replacements. Thanks again.

b said...

This is a great write up. I very much enjoyed reading the article. The way you describe nicotine in regular nicotine users sounds very similar to the effects of modafinil. With many college kids now taking modafinil to help their cognitive ability, how much do we know about it's mechanism of action in the PFC? Does it appear to be similar?

John R. Polito said...

Although a wonderful explanation of neuronal function I'm surprised that anyone so aware of nicotine's function within the body would fail to mention any of its ill effects. Nicotine is a super toxin that drop for drop is more deadly than arsenic, strychnine or diamond back rattlesnake venom. The amount entering the bloodstream via a single cigarette (about 1 mg) is sufficient to kill a one pound rat. Nicotine actually eats up and destroys brain gray matter, the very cells this article argues are benefitted. You may also want to teach readers nicotine's role in promoting cancer and circulatory disease.

b said...

Please, enlighten us John. I am interested in both sides. Can you give any references?

Lizzie said...

Sorry, I'm new at this blogging thing and I just realized I had these comments...I'll try to address them now...

I should start by saying that nicotine affects many parts of your brain. Most of the addictive effects are mediated by nicotine's effects on the release of another neurotransmitter, dopamine, in the brain's "reward centers." This paper, and this post, focused on the effects on attention mediated by the PFC, because that is really the only cognitive benefit that has been reliably observed.

Jay, I've never been a smoker, so I can't actually attest to this, but I think the "stupid-enhancing" effects of nicotine withdrawal are short-lived. The reason nicotine enhances cognitive abilities in smokers is that their brains are accustomed to nicotine, and high levels of ACh activity. Without nicotine, their neuronal circuits are functioning "suboptimally," and need the nicotine to get back to baseline. In contrast, non-smokers are already performing "optimally," and perturbing their ACh levels will only bring their abilities to a suboptimal level (except, possibly, in extremely attention-demanding situations, in which they would already be performing suboptimally, and nicotine may help).

I'm not sure what you mean by "nicotine cloud"--that it affects the entire brain at once? If so, I would think that nicotine replacements would have the same effects, because they enter the brain via the bloodstream as opposed to being released in a regulated fashion from individual neurons, but with a slightly different timecourse (because the modes by which the chemical enters the bloodstream are different). Also, the effects may be significantly different because of the psychological effects associated with the act of smoking versus putting on a patch.

B, it isn't really well known how modafinil acts (I posted on it about a month ago), but I think it's pretty different. Modafinil doesn't seem act on ACh, although it does seem to increase levels of dopamine and norepinephrine, which are also increased with nicotine. Its effects are also more directly related to alertness and "wakefulness," as opposed to attention (although it is occasionally prescribed for ADHD). But I think the pharmaceutical companies are pretty tight-lipped about it...

John, you bring up a good point...nicotine is a potent toxin, and the fatal dose of pure nicotine in humans is 40-60 mg (1-2 drops). However, the smoke from a filtered cigarette contains only 0.2 and 1.0 mg (1.2-2.4 in an unfiltered), up to 90 percent of which will be absorbed by the smoker. Furthermore, smokers usually spread their nicotine intake throughout the day, so the dose in a human smoker at any one time is pretty low.

Also, as far as I'm aware, nicotine is not directly carcinogenic (although it may indirectly facilitate cancer by inhibiting apoptosis), and I haven't seen anything about direct effects on "gray matter" survival (at least in any biologically relevant dose). Do you have more information on this?

I should conclude all this by saying that I don't smoke, I'm in favor of cigarette taxes and banning cigarettes in bars, I don't like standing by people who are smoking, and I tell all of my friends to quit. But it's important to not blindly demonize everything associated with cigarettes, including its addictive (and therefore most "evil") component. Nicotine does have some cognitive enhancing effects that may significantly improve the quality of life for people with certain diseases, and so it's important to understand how it works so we can develop drugs specific to these beneficial effects.

Thanks for reading!

Unknown said...

Several things do come to mind, both from the original post and the repy to the commnets by Madam Fathom. First of all, I am following the many developments in all areas of Nanotechnology research, most specifically in the field of energy. However, the developments in the medical field are of interest, too. As a former smoker who did quite cold turkey over a decade ago I know how hard it is. I also now realize it did help me with my cognative powers and did inhance my attention level.

So now, with nanotechnolgy moving forward, perhaps you might do some research into using nanomaterials to enhance the synaptic reactions in both the transmitter and the receptor. Also, not withstanding Jake 2.0 and the Borg, perhaps the brain-computer interface being developed within Nanotechnology could be useful. One might consider Brain-computer interface wikipedia and this little study.

I am also new with blogging, my blog being http://chtank.blogspot.com/.
But you see from my blog(s), I am primarily concerned with the physical sciences.

Anonymous said...

Nicotine causes chemical and biological changes in the brain. Although it is less dramatic than heroin or cocaine, the strength of the addiction is just as powerful. It is a “reinforcing” drug, which means that users desire the drug regardless of the damaging effects.The human body builds a tolerance to nicotine and the effect of the drug is reduced over time. As a result, regular smokers can inhale greater amounts of smoke and toxins without showing immediate effects (ie. coughing, nausea).Nicotine is considered addictive because it alters brain functioning and because people use it compulsively. Addiction to nicotine is not immediate – it may take weeks or months to develop.

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