This is a summary of a of a review-piece published in the prestigious science journal Trends in Pharmacological Sciences in 2010 ([link]) entitled "Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis". The publication was authored by Yann Mineur and Marina Picciotto, and discussed the connection between smoking, nicotinic receptors, and depression.

Below I will summarise the main points of the review piece, providing additional information and explanations along the way.

It is well know that there exists a relationship between smoking and depression, and especially that depressed individuals are more likely to take up and maintain a smoking habit. There are different explanations which could account for this fact. Perhaps people who are depressed are more reckless. Or perhaps they're self-medicating.

One of the most important and best known of the chemicals that are taken up by the body when a person smokes is the chemical nicotine. Nicotine is a drug, which means it interacts chemically with the body's cells. Nicotine reaches special cells called neurons (which make up our brain and nervous system) and bind to some types of cholinergic receptors.

Neurons are cells that can be imagined as small balls with wires sticking out to other neurons. At the place where neurons touch they send signals to each other, and they receive signals by receptors which they have on their surfaces. There are many different classes of receptors, and they include cholinergic receptors. There are different types of cholinergic receptors, and a major type includes those that can be activated by nicotine. Cholinergic receptors that can be activated by nicotine are called nicotinic receptors, and are abbreviated as nAChR (nicotinic acetylcholine receptors).

When a person smokes tobacco, nicotine is absorbed into the blood, is taken up into the brain, and then reaches specific places in the brain where it turns on nAChR, causing those neurons to signal.

There is evidence supporting the idea that nicotine might have a limited anti-depressant effect by acting on cholinergic receptors. It has been observed that nicotine can have an anti-depressant effect and that nicotine can desensitize nAChR. To desensitize means to reduce the activity of the nAChR, for example perhaps at first the nAChR signal at 100%, but after being desensitized they only signal 50% as much, and so they have a smaller effect.

But why would desensitization of nAChR have an effect on depression?

Depression is obviously a very complex phenomenon, and researchers sometimes attempt to provide models to explain particular mechanisms of depression. One such attempt is the hypercholinergic hypothesis of depression. That hypothesis states that too much (i.e. hyper-) cholinergic receptor activity (i.e. hypercholinergic) results in depression.

Does this explain everything? Not quite, and there are various other details that need to be squared with this hypothesis. This includes the facts that (A) heavy smoking correlates with suicide, (B) smoking cessation increases depression but reduces stress. (A) suggests that there is no dose dependent response, in other words, it's not like the more you smoke the less depressed you become. Instead, it seems like the opposite is true, and the more depressed a person is the more they are likely to smoke.

Perhaps smoking causes short term activation of nAChR, long term increase in nAChR number, but also long term decrease in nAChR activity (i.e. signalling). (B) can now be explained as a consequence of altering nAChR numbers without regular stimulation (i.e. when you stop smoking there is still a period in which you have extra nAChR hanging about).

So is that the answer? Is that how smoking affects depression? Maybe. Definitely smoking does affect depression, and definitely affecting nAChR with other drugs can have anti-depressant affects. However despite what was said above, it's still controversial whether the affects being observed are due to the desensitization observed, or whether the desensitization occurs in parallel. Various other explanations have been offered: The effects could be due to nicotine affecting other signalling systems (in particular monoanime systems). Also, it's possible that the mechanism depends on the actual activation of nAChR by nicotine, perhaps the activation itself sets in motion other events which have the long-term effect of anti-depression.

Another problem is to explain why not all people respond equivalently to nicotine or AChR activation. It seems likely that there are various hereditary and environmental factors that determine the interaction between smoking, nicotine, and depression. It's also quite certain that nicotine will have many unforeseen effects which could contribute to a person's mood beyond the effect on nAChR signalling.

In summary: Depressed individuals may self-medicate by smoking. Smoking results in nicotine reaching the brain and acting on nicotinic acetylcholine receptors, where it has the short term effect of stimulating those receptors, but the long term effect of desensizing them. It has been hypothesized that the desensitization of nicotinic receptors is key to the anti-depressant affect observed in smokers and in drugs that target nicotinic receptors.

So what's the take-away message?*

First of all the link between smoking and depression seems to be due to depressed people self-medicating. Does that mean that smoking can/should be used as an anti-depressant? Smoking and nicotine do have an anti-depressant effects, but not as impressive as those reported for the more common pharmaceuticals. Should you convince yourself to smoke to deal with depression, please keep in the following in mind: the effect is not dose-dependent. The anti-depressant effect is a long-term effect primarily, and is not increased by smoking more. In fact, it would be far more efficient to plaster on a nicotine patche to get the same effect while reducing the other health risks. If you are depressed and smoking I think that it's important that you be aware of these facts.

Next there's the link between cholinergic signalling (including nAChR signalling) and depression. I don't think any one at this point would dispute that modulating cholinergic signalling can affect depression. As for the mechanism by which this might occur, although the authors of the paper emphasize the role of nAChR desensitization I'm yet to be convinced that this is an adequate explanation. I don't have any problem with the evidence the authors referenced, but am aware that in the case of monoamine-mediated anti-depression the mechanism of action is appreciated to be far more complex than a simple imbalance of neurotransmitters or receptor potency (although these are likely contributing factors). I'm not sure whether the authors simply elected not to discuss down stream mechanisms (like neurogenesis; new neuron formation), or whether the problem of cholinergic transmission is seen as a modular component of depression which can be considered in isolation. Watch this space I suppose.

That said, nAChR targeting drugs for depression is quite exciting. It won't be a panacea for depression, but at this point every step counts.

* Although I have some biology background, I am not closely familiar with this field. Thus these opinions should be taken for what they are.

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