The Neurobiology of Nicotine
Introduction
Nicotine, the psychoactive substance found in cigarettes and other similar products, has a wide range of effects on peoples’ neurobiology and their behavior. This can include both positive and negative effects. Many of the mechanisms behind the effects that it has were presented throughout the semester in the chapters for our Neurobiology class. Some of the topics include channel structure, the resting membrane potential, neurotransmitter release, second messengers, long term potentiation, sensitization, and nerve regeneration. All of these things can be influenced by nicotine use, and most of the time it results in a change in behavior.
Unit 1: Biological and Electrical Properties of Neurons
Nicotinic Acetylcholine Receptor Structure
Nicotinic acetylcholine receptors are a type of ionotropic receptor that also acts as a channel which can open up to allow ions such as calcium and sodium in. We discussed the structure of ion channels in chapter 4. Below is a photo of nicotine receptors from the article by Dani (2015). You can see the five α subunits that make up each channel and the pore that forms in the center where ions pass through.
To the left is a side view of nAChR channels from the article. This shows how they transverse the plasma membrane and extend into the inside of the cell. Each channel is made up of multiple subunits as well as certain filters that only allow certain ions though. When nicotine binds to their receptors on these channels, they open up the pore and allow ions into the cell.
Using Patch Clamp Technique to Measure the Effects of Nicotine
In the article by Page et al. (2018), they observed the effect that both chronic and acute administration of nicotine has on catecholamine neurons. These neurons are responsible for the stress response as well as reflexes in the gastric and cardiovascular systems. In their study, they used the patch-clamp method, like we learned about in chapter 4, to measure the current of ions through channels on a piece of the membrane. How the patch clamp is set up is shown to the left. This method controls the resting membrane current and holds it at a certain voltage to see the effect on certain channels. As we learned from chapter 2, the resting membrane potential is the voltage at which the membrane is as rest. It is produced by the concentration and electrochemical gradients of ions such as Na and K. In the experiment, the membrane depolarized, or got more positive, when it was treated with nicotine. They explained that this depolarization caused glutamate to be released, leading to a variety of effects that these neurons are responsible for such as cardiovascular function and the stress response.
Unit 2: Neurotransmission
Nicotine and Neurotransmitter Release
Nicotine consumptions can lead to changes in cognition due to the type and amount of neurotransmitter released. In the article by Singer et al. (2004), they observed that nicotine administration resulted in an increase of dopamine, serotonin, and norepinephrine release in the hippocampus and the cortex. As we discussed in chapter 6, these neurotransmitters are known as catecholamines and they have a variety of effects throughout the brain. The researchers also discussed how serotonin and norepinephrine release in certain areas of the brain can result in the release of dopamine in other areas. Nicotine was also shown to increase the synthesis of these neurotransmitters throughout different areas of the brain. The graphs below illustrate the increases in dopamine and serotonin following the administration of nicotine.
Due to the release of these neurotransmitters in areas of the brain associated with cognition, this research suggests that nicotine may provide short-term improvements in learning and memory.
Nicotine’s Effect on Alzheimer’s Disease
This article by Oddo et al. (2005) is about the effect that nicotine administration has on the formation of beta-amyloid plaques and tau phosphorylation in a mouse model of Alzheimer’s disease. Nicotine binds to nicotinic acetylcholine receptors (nAChRs), and in this study the alpha subtype (α7nAChRs). These receptors are ionotropic receptors, meaning when a ligand binds to them, the channel that they are a part of opens up and allows ions such as Calcium in. The image to the left shows an ionotropic, or channel-linked receptor, which nicotinic receptors are.
Alzheimer’s disease can decrease the number of these receptors in the brain, especially in regions where they are most common such as the frontal cortex. One of the most common features of the disease are beta-amyloid plaques. These plaques can bind to α7nAChRs, enter the cell, and also cause more calcium to enter the cell. As shown in chapter 7, when Ca enters the cell, it can act as a second messenger and can cause certain protein kinases to be activated. Protein kinases are enzymes that phosphorylate and activate different proteins.
In this model of Alzheimer’s disease, the kinase that is activated by Ca is the p38-MAP (mitogen-activated protein) kinase. This leads to an increase in phosphorylation of the tau protein which builds up in the brain of people with Alzheimer’s as neurofibrillary tangles. In this second image above from chapter 7, you can see how second messengers, such as Ca, activate kinases which phosphorylate proteins.
Overall, in this mouse model of Alzheimer’s disease, nicotine administration caused Ca to enter the cell through nAChRs which was then able to activate protein kinases to phosphorylate tau, causing it to build up. The binding of beta-amyloid to these receptors also allowed more Ca into the cell and continue to activate kinases. This research suggests that smoking may worsen the effects of Alzheimer’s disease, while some other research suggests the opposite.
Nicotine and Development
Nicotine can have a number of negative side effects in the developing newborn when used by the mother. In the article by Abreu-Villaça et al. (2018), they investigated the effect that both alcohol and nicotine consumption in pregnant mice would have on their offspring’s cognition. They found that the offspring of these mice were hyperactive and had deficits in their learning and memory. They discovered that this was related to the amounts of the second messengers cAMP and cGMP in different parts of their brain such as the hippocampus and the cortex. As discussed in chapter 7, these second messengers target protein kinases which go on to phosphorylate different proteins. Nicotine exposure to mice during development resulted in a decrease in cAMP and cGMP, which limited the phosphorylation of CREB, leading to the altered expression of genes that encode for plasticity. Below are graphs showing the significant reductions of cAMP and cGMP in the nicotine and nicotine and alcohol group that occur in the cerebral cortex.
This research shows the mechanisms behind the devastating effects of nicotine and alcohol exposure during development.
Unit 3: Neuroplasticity
Nicotine and LTP
In the article by Mansvelder & McGehee (2000), the authors discuss how nicotine can lead to long term potentiation in dopaminergic neurons in the ventral tegmental area. Long term potentiation is an increase in synaptic strength which is mediated by NMDA receptors. In the article, the researchers found that presynaptic neurons in the VTA that contained nicotinic ACh receptors and were exposed to nicotine allowed more Ca to enter the presynaptic terminals, causing more glutamate to be released in the synapse. This increased glutamate release activated more NMDA and non-NMDA receptors such as AMPA on the postsynaptic cell. Through this increased activation of receptors, more Ca is then allowed to enter the cell, activating kinases such as Ca calmodulin kinase II, resulting in phosphorylation, causing more receptors to become added to the membrane, increasing sensitivity. This process can be seen in the photo above from chapter 8. The results of their experiment showing nicotine resulting in LTP in the postsynaptic cell is shown below.
In figure b., you can see an increase in excitatory post synaptic current caused by the rapid stimulation of nicotinic ACh receptors by nicotine. Figure c. also shows LTP caused by nicotine administration.
The article also discusses how nicotinic ACh receptors on the presynaptic neuron allow the Mg plug in the NMDA receptors to be opened sooner, further aiding in LTP. The Mg plug in the NMDA receptors can be seen in the photo to the left, also from chapter 8. Through LTP and synaptic plasticity in the reward center of the brain, addiction can occur from substances such as nicotine through the manipulation of synapses.
Nicotine and Nerve Regeneration
In animal models, nicotine has been shown to have anti-inflammatory and neuroprotective effects on injured nerves. In the article by Wang et al. (2019), they showed how nicotine can promote nerve regeneration by reducing the amount of pro-inflammatory cytokines such as TNF-α and IL-1β around damaged sciatic nerves. In chapter 25 we discussed how inflammation in the area of the damaged nerve can hinder regrowth. Nicotine was shown to increase the expression of GAP-43 as well, which we also discussed in chapter 25 as being a growth associated protein that is secreted by Schwann cells and helps with nerve regrowth in peripheral axons. The researchers discussed that this anti-inflammatory and pro-regeneration effect occurs through the α7nACh receptor. In the images to the left and below from the article, you can see how nicotine compared to other control substances in terms of reducing pro-inflammatory cytokines and increasing the expression of GAP-43 in the area of injury to the sciatic nerve in the mouse model.
This research suggests that through the reduction of pro-inflammatory cytokines and the increased expression of GAP-43, nicotine may be able to provide support for nerve regeneration through the action of α7nAChRs.
Nicotine and Behavior Sensitization
In multiple studies, nicotine has been shown to increase motor sensitization. In the article by Schoffelmeer et al. (2002), they demonstrated that chronic nicotine exposure in mice resulted in the sensitization of motor behaviors. As we discussed in chapter 8, sensitization results in an increase of a behavior due to repeated stimulation. In this study, the researchers found that repeated nicotine exposure resulted in an increase in motor behavior compared to the control. In the graph to the left, you can see the effect that sensitization has on the distance traveled over time. In the first graph, the introduction of nicotine to mice that were previously sensitized to nicotine traveled more distance than those that had no previous experience with nicotine, though they both experienced an increase. In the second graph, the mice that were sensitized to nicotine traveled an even greater distance when later exposed to amphetamines. This shows how nicotine administration also sensitized the synapse to other drugs like amphetamines .The researchers suggest that an increase in nicotine results in an increase in dopamine and glutamate transmission in the VTA. This article provides some explanation for the addictive properties of nicotine, the interaction of these sensitized receptors and other drugs, and some of the behaviors associated with them.
Conclusion
In conclusion, nicotine can influence behavior through biological processes that we learned about throughout the semester such as long term potentiation, sensitization, nerve regeneration, second messengers, neurotransmitter release, the resting membrane potential, and channel structure. Nicotine use can influence these processes and can effect a variety of things such as the progression of Alzheimer’s disease, brain development, addiction, and other behaviors.
References
Abreu-Villaça, Y., Carvalho-Graça, A. C., Skinner, G., Lotufo, B. M., Duarte-Pinheiro, V., Ribeiro-Carvalho, A., Manhães, A. C., & Filgueiras, C. C. (2018). Hyperactivity and memory/learning deficits evoked by developmental exposure to nicotine and/or ethanol are mitigated by cAMP and cGMP signaling cascades activation. Neurotoxicology, 66, 150–159. https://doi.org/10.1016/j.neuro.2018.04.003.
Dani J. A. (2015). Neuronal nicotinic acetylcholine receptor structure and function and response to nicotine. International Review of Neurobiology, 124, 3–19. https://doi.org/10.1016/bs.irn.2015.07.001.
GSK Health Partner. (n.d.). The Science Behind Nicotine Dependence. Retrieved from https://www.gskhealthpartner.com/en-us/respiratory-health/conditions/smokers-health-conditions-home/smoking-cessation/nicotine-dependance/.
Mansvelder, H. D., & McGehee, D. S. (2000). Long-term potentiation of excitatory inputs to brain reward areas by nicotine. Neuron, 27 (2), 349–357. doi: 10.1016/S0896–6273(00)00042–8.
Oddo, S., Caccamo, A., Green, K. N., Liang, K., Tran, L., Chen, Y., Leslie, F. M., & LaFerla, F. M. (2005). Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 102(8), 3046–3051. https://doi.org/10.1073/pnas.0408500102.
Page, S. J., Zhu, M., & Appleyard, S. M. (2019). Effects of acute and chronic nicotine on catecholamine neurons of the nucleus of the solitary tract. American journal of physiology. Regulatory, Integrative and Comparative Physiology, 316(1), R38–R49. https://doi.org/10.1152/ajpregu.00344.2017.
Schoffelmeer, A. N., De Vries, T. J., Wardeh, G., van de Ven, H. W., & Vanderschuren, L. J. (2002). Psychostimulant-induced behavioral sensitization depends on nicotinic receptor activation. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience, 22(8), 3269–3276. https://doi.org/10.1523/JNEUROSCI.22-08-03269.2002.
Singer, S., Rossi, S., Verzosa, S., Hashim, A., Lonow, R., Cooper, T., …Lajtha, A. (2004). Nicotine-induced changes in neurotransmitter levels in brain areas associated with cognitive function. Neurochemical Research, 29(9), 1779–1792. doi:10.1023/b:nere.0000035814.45494.15.
Wang, D., Gao, T., Zhao, Y., Mao, Y., Sheng, Z., & Lan, Q. (2019). Nicotine exerts neuroprotective effects by attenuating local inflammatory cytokine production following crush injury to rat sciatic nerves. European Cytokine Network, 30(2), 59–66. https://doi.org/10.1684/ecn.2019.0426.
