Research Article: Alcohol’s Actions on Neuronal Nicotinic Acetylcholine Receptors

Date Published: , 2006

Publisher: National Institute on Alcohol Abuse and Alcoholism

Author(s): Tiffany J. Davis, Christopher M. de Fiebre.

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Abstract

Although it has been known for many years that alcoholism and tobacco addiction often co-occur, relatively little information is available on the biological factors that regulate the co-use and abuse of nicotine and alcohol. In the brain, nicotine acts at several different types of receptors collectively known as nicotinic acetylcholine receptors (nAChRs). Alcohol also acts on at least some of these receptors, enhancing the function of some nAChR subtypes and inhibiting the activity of others. Chronic alcohol and nicotine administration also lead to changes in the numbers of nAChRs. Natural variations (i.e., polymorphisms) in the genes encoding different nAChR subunits may be associated with individual differences in the sensitivity to some of alcohol’s and nicotine’s effects. Finally, at least one subtype of nAChR may help protect cells against alcohol-induced neurotoxicity.

Partial Text

Nicotine interacts with several different nAChR subtypes in the brain. All of these nAChRs belong to a family of receptors that are collectively called ligand-gated ion channel receptors. Ions are atoms or molecules that carry an electrical charge because they possess different numbers of negatively (electrons) and positively (protons) charged particles. Common examples of ions include sodium (Na+),1 chloride (Cl−), potassium (K+), and calcium (Ca2+). The concentration of ions on the inside of neurons (nerve cells) versus the outside of neurons is strictly regulated. Typically, the concentration of K+ ions is greater inside the neuron than on the outside, whereas the concentrations of Na+, Cl−, and Ca2+ are greater outside the neuron than on the inside. Ligand-gated ion channel receptors, such as nAChRs, form pores or channels that, when opened, allow specific ions to flow into or out of neurons. For example, acetylcholine and certain drugs, such as nicotine, cause nAChRs to open (i.e., they “gate” the channel), thereby allowing Na+ and/or Ca2+ to enter a neuron. The resulting transient change in the internal ion concentration modulates the neuron’s excitability—that is, its ability to fire and transmit a nerve signal by releasing neurotransmitters that act on other neurons. In addition, the changes in ion concentrations provide specific signals or information to the affected neuron.

Alcohol and nicotine both act on the brain, and because so many people use and abuse both drugs it is likely that both drugs act on at least some of the same brain structures. One of the most probable places for alcohol and nicotine to interact is at nAChRs. Over the last two decades, numerous studies have shown that alcohol affects many different types of ion channels, including ligand-gated ion channel receptors (Narahashi et al. 2001). Moreover, researchers have demonstrated that alcohol can directly act on different nAChR subtypes. Many of these studies have been done using cloned receptors that were introduced into and produced (expressed) in frog eggs (Xenopus oocytes). Because these eggs do not normally express nAChRs, they provide a model system in which only the introduced nAChR subtype is produced. This design allows investigators to study, for example, alcohol’s or nicotine’s effects on one specific nAChR subtype without having to distinguish between diverse effects on different receptor subtypes.

Nicotine’s effects at nAChRs are complex. Nicotine not only activates nAChRs but also can quickly inactivate these receptors via a process called desensitization.3 In fact, Brody and colleagues (2006) recently reported that with the amount of nicotine consumed by most cigarette smokers, the majority of α4β2 nAChRs should be in a continuous state of desensitization. It is not clear whether the nicotine-induced desensitization of nAChRs causes a smoker to no longer experience some of the effects of nicotine or if it actually produces an effect that smokers seek. Interestingly, Marszalec and colleagues (1999) have shown that alcohol interferes with the nicotine-induced desensitization of α4β2 nAChRs. As a result, alcohol may reverse some of the desensitization caused by smoking at these nAChRs. Whether this contributes to the co-use of alcohol and nicotine is not known.

Studies conducted in the early 1980s first demonstrated that chronic nicotine treatment can cause an increase in the number of nAChRs in the brains of rodents. Moreover, several of these studies indicated that genetic factors influence the degree to which nicotine increases nAChR numbers in a given individual. Finally, the degree of increase differed among different brain regions and nAChR subtypes (Marks et al. 1991). In general, nicotine induced greater increases in α4β2 nAChR numbers than in α7 nAChR numbers.

For many years, it has been established that a person’s risk of becoming alcohol dependent is determined in part by that person’s genetic makeup. More recently, researchers also demonstrated that the risk of becoming a smoker (nicotine dependent) is determined in part by a person’s genetic makeup as well. The common co-occurrence of drinking and smoking leads to the question of whether the same or similar genes control the development of both alcohol and nicotine dependence.

Researchers also have begun to investigate if and how specific nAChR subtypes contribute to and modulate alcohol’s brain-damaging (i.e., neurotoxic) effects. (For more information on the interactions between alcohol and nicotine, as well as between alcohol and nAChRs, in modulating alcohol’s neurotoxic effects, see the article by Funk and colleagues in this issue.) Studies using cultured neurons derived from α7 nAChR knock-out mice demonstrated that the absence of α7 nAChR renders neurons more susceptible to alcohol’s toxic effects (de Fiebre and de Fiebre 2005). This observation suggests that α7 nAChRs may somehow protect the cells against the neurotoxic properties of alcohol and complements findings that α7 nAChRs modulate the neurotoxicity associated with alcohol withdrawal (Mulholland et al. 2003).

Although this review may give the impression that much is known about the nAChRs involved in modulating some of the interactions between alcohol and nicotine, great gaps in knowledge remain regarding these interactions and how they modulate the acute and chronic actions of both drugs. Moreover, researchers still do not know how these interactions modulate the development and maintenance of co-dependence on alcohol and tobacco. Elucidation of these processes is of utmost importance because smoking has been identified as one of the most important risk factors for alcoholism. Despite the importance of smoking/nicotine use in alcoholism, only a small fraction of research into the biology of alcohol has focused on the mechanisms involved in modulating the co-use and abuse of alcohol and nicotine. It is imperative that researchers gain a greater understanding of the role of nAChRs in modulating alcohol–nicotine interactions in order to more clearly understand the factors involved in the development of alcoholism. Such an understanding should lead to more effective treatments for alcohol and/or tobacco dependence.

 

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