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.

Keywords: acetylcholine; alcoholism; mesolimbic dopamine system; nicotine; nicotinic receptors.

Figure 1

Neuronal nAChR Structure. (A) Membrane topology of a neuronal nAChR subunit. Each nAChR subunit contains four transmembrane domains (M1-M4), an extracellular amino- and carboxy-terminus, and a prominent M3-M4 intracellular loop of variable length. (B) Five subunits coassemble to form a functional subunit. (C) Homomeric receptors consist of α subunits only and usually have low affinity for agonist. To date, only mammalian α7, α9, and α10 (not shown) subunits may form functional homomers. (D) The majority of high affinity nAChRs are heteromeric and consist of a combination of α and β subunits. Importantly, multiple α subunits may coassemble with multiple β subunits in the pentameric nAChR complex (illustrated here by α4α6β3β2). ACh binding sites are depicted as red triangles.

Figure 2

Neuronal nAChR expression in the reward pathway. (A) Sagittal rodent section illustrating the simplified mesocorticolimbic and habenulo-peduncular circuitry. Known neuronal nAChR subtypes expressed in different nuclei are indicated [for a review see (Millar and Gotti, 2009)]. (B) In the VTA, alcohol stimulates DAergic neurons at least, in part, via nAChR activation. Ethanol increases ACh release (red arrow, presumably through cholinergic projection from the LDT/PPTg) which in turn activates nAChRs on DAergic neurons driving activity. In addition, ethanol potentiates ACh activation at high affinity α4β2* nAChRs (red plus sign). The effect of alcohol on additional nAChRs in the VTA is unknown. This confluence of events in combination with other effects of alcohol in the VTA ultimately increases DA release in NAc (red arrow). VTA, Ventral tegmental area; NAc, Nucleus accumbens; PFC, Prefrontal cortex; LH, Lateral habenula; MH, Medial habenula; IPN, Interpeduncular nucleus; LDT, Lateral dorsal tegmentum; PPTg, Pedunculopontine tegmentum.