Why is Cigarette Smoking So Addictive?

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Everyone knows that cigarette smoking is terrible for your health. Everyone knows that smoking causes cancer, heart disease, stroke, emphysema, bronchitis, vascular disease, cataracts, impotence, and other health problems. The World Health Organization estimates that more than four million deaths each year are attributable to smoking. Nonetheless, the number of smokers in the world increases each year and anyone who has tried to give it up knows that that is a very hard thing to do. And we know that it is to get the nicotine in the cigarettes that people suck the rest of those hazardous chemicals onto their delicate internal membranes and into their bodies.

So what accounts for that craving for nicotine that can take on monstrous power after only a few cigarettes? The answer is in the nicotine-mediated stimulation and regulation of the ultimate feel-good chemical in the brain, dopamine (DA). Part of the mechanism behind nicotine’s ability to maintain stimulation of the brain’s reward centers after even a brief exposure was described by Dr.’s Daniel McGehee and Hulbert Mansvelder, at the University of Chicago, in an article published in Neuron in 2000 (1). When nicotine binds to neurons in a certain area of the brain, these neurons quickly secrete some DA, which acts on the “reward” areas of the brain and is perceived as very pleasurable. But the receptors on these cells lose their sensitivity to the nicotine in a short time, mere seconds to a few minutes, and the cells stop secreting DA. End of story, fun’s over, right? Nope. As it turns out, this same type of receptor for nicotine also occurs on presynaptic terminals in this same area of the brain. When they are activated by nicotine, they cause the release of a signal molecule, glutamine. This newly released glutamine can act on certain DA neurons to stimulate them to release more DA. This activation of DA neurons by glutamine results in continued release of DA for hours, a case of long-term potentiation of excitatory input. So even though a person was only exposed to the nicotine for a few minutes, its pleasurable effects can continue for some time in this way. This can explain the long-term excitation of brain reward areas induced by brief nicotine exposure. The whole mechanism is similar to events seen during learning and memory and may be an important early step in the development of addiction.

A second part of the puzzle is why this stimulation of DA release isn’t turned off sooner. As explained by this same group in an article published in Neuron in 2002 (2), the body has a mechanism to shut down galloping DA production and that mechanism is stimulated by nicotine. Nicotine binds to and activates receptors on cells that then release the most potent inhibitory neurotransmitter in the central nervous system, gamma-aminobutyric acid (GABA). Briefly. Yes, unfortunately, the receptors for nicotine that then turn on release of GABA that acts to shut down DA release are also desensitized to nicotine fairly soon after contact with it. But the activation of glutamine release continues and its activation of DA release can continue as GABA release diminishes. So the longer term result is more DA being produced through the excitatory release of glutamine via activated nicotine receptors.

Thus it seems that a person’s intense desire for the nicotine in cigarettes can be explained simply by the dance of the drug with the receptors that will embrace it. At first nicotine finds the receptors on the DA neurons which are happy to bind it and then are stimulated to release the DA. But they soon tire of the nicotine, and are no longer stimulated by it. Then there the receptors that bind and maintain their infatuation with the nicotine, releasing glutamine, and causing release of DA, for hours. But thirdly, there are the receptors that bind nicotine and are activated to release the powerfully negative signal, GABA. But these receptors soon lose interest and leave the nicotine to interact primarily with the excitatory glutamatergic path.

And so, from these complicated interplays between molecules come a person’s powerful desire for a cigarette. Life-destroying addictions are born of such molecular events. Is it necessarily true that we must obey the dictatorship of molecular interactions, that we must do whatever it takes to maintain our dopamine levels? Is it not possible, then, that a person’s powerful thoughts and desires, say, not to be a slave to a mere muck of molecules, or his choice for a drug-free life, can modify the consequences of those molecular interactions? Can such strong, self-determined thoughts change a person’s response to the cigarette so that he no longer finds pleasure in it but aversion or indifference? Why are some people strongly and immediately addicted after only a few cigarettes, while others smoke for a week and walk away for a lifetime? Why are some long-time smokers totally helpless when it comes to trying to give up the habit, but others can give it up easily, and still others persevere through repeated failures until they eventually succeed? While it may be true, as science tells us, that our mental state, our craving for a nicotine-packed cigarette, can be stimulated by molecular interactions initiated by the binding of that drug to receptors in our brain, isn’t it also true that we are not bound, do not have to obey, can ignore or rise above this tyranny? Perhaps a human being is more than a mere bag of molecules, after all.

References:
(1) Mansvelder, H.D. and McGehee, D.S. (2000). Long-term potentiation of excitatory inputs to brain reward areas by nicotine. Neuron 27, 349-357.

(2) Mansvelder, H.D., Keath, J.R., and McGehee, D.S. (2002). Synaptic mechanisms underlie nicotine-induced excitability of brain reward areas. Neuron 33, 905-919.