Neuronal Nicotinic Acetylcholine Receptors: Common Molecular Substrates of Nicotine and Alcohol Dependence

Abstract

Alcohol and nicotine are often co-abused. As many as 80–95% of alcoholics are also smokers, suggesting that ethanol and nicotine, the primary addictive component of tobacco smoke, may functionally interact in the central nervous system and/or share a common mechanism of action. While nicotine initiates dependence by binding to and activating neuronal nicotinic acetylcholine receptors (nAChRs), ligand-gated cation channels normally activated by endogenous acetylcholine (ACh), ethanol is much less specific with the ability to modulate multiple gene products including those encoding voltage-gated ion channels, and excitatory/inhibitory neurotransmitter receptors. However, emerging data indicate that ethanol interacts with nAChRs, both directly and indirectly, in the mesocorticolimbic dopaminergic (DAergic) reward circuitry to affect brain reward systems. Like nicotine, ethanol activates DAergic neurons of the ventral tegmental area (VTA) which project to the nucleus accumbens (NAc). Blockade of VTA nAChRs reduces ethanol-mediated activation of DAergic neurons, NAc DA release, consumption, and operant responding for ethanol in rodents. Thus, ethanol may increase ACh release into the VTA driving activation of DAergic neurons through nAChRs. In addition, ethanol potentiates distinct nAChR subtype responses to ACh and nicotine in vitro and in DAergic neurons. The smoking cessation therapeutic and nAChR partial agonist, varenicline, reduces alcohol consumption in heavy drinking smokers and rodent models of alcohol consumption. Finally, single nucleotide polymorphisms in nAChR subunit genes are associated with alcohol dependence phenotypes and smoking behaviors in human populations. Together, results from pre-clinical, clinical, and genetic studies indicate that nAChRs may have an inherent role in the abusive properties of ethanol, as well as in nicotine and alcohol co-dependence.

Acute Ethanol Inhibits Dopamine Release in the Nucleus Accumbens via α6 Nicotinic Acetylcholine Receptors

“…4A) in vivo. It has previously been shown that the nonspecific nAChR antagonist MEC (Peng et al, 2013) reduces ethanol consumption and blocks ethanol-induced DA release in the NAc (Blomqvist et al, 1993;Hendrickson et al, 2013). To understand how nAChRs contribute to ethanol's inhibitory effects on DA in the NAc, we evaluated the effects of MEC on evoked DA signals in anesthetized mice.…”

“…Often taken in concert (Miller and Gold, 1998), tobacco and alcohol are leading causes of preventable death in the United States (Danaei et al, 2009). Approximately 80% of alcoholics are also smokers (Hendrickson et al, 2013;Taylor et al, 2013b), and heavy smokers are 10 times more likely to be alcoholics (DiFranza and Guerrera, 1990). Although smoking rates in the general population have decreased in recent decades, the use of nicotine has remained high (∼70%-75%) in individuals who regularly use alcohol (Meyerhoff et al, 2006;Hendrickson et al, 2013).…”

“…Alcohol abuse is prevalent in today's society, causing an economic burden to the United States of hundreds of billions annually in direct costs alone (Mokdad et al, 2004;Hendrickson et al, 2013). Often taken in concert (Miller and Gold, 1998), tobacco and alcohol are leading causes of preventable death in the United States (Danaei et al, 2009).…”

“…It has recently been theorized that because of the high percentage of codependence with these drugs, both ethanol and nicotine may act on similar targets in the brain, specifically nicotinic acetylcholine receptors (nAChRs) on presynaptic GABAergic neurons or DAergic terminals (Hendrickson et al, 2013;Taylor et al, 2013b). Ethanol appears to activate DAergic neurons in the VTA through an interaction at nAChRs (Soderpalm et al, 2009).…”

Nicotine and Tobacco as Substances of Abuse in Children and Adolescents

“…Studies indicate that ethanol potentiates the response of high-affinity nAChRs to both acetylcholine and nicotine. 32 Even small amounts of alcohol are known to boost nicotine effects, inducing subjects to smoke more. A recent study in a mouse model examining the effects of nicotine on cocaine abuse has provided a biological mechanism to support the gateway theory by showing that nicotine increases the expression of the FosB gene (which has been related to addiction) and increases the vulnerability to cocaine dependence.…”