Recent advances in understanding nicotinic receptor signaling mechanisms that regulate drug self-administration behavior

Abstract

Tobacco smoking is one of the leading causes of disease and premature death in the United States. Nicotine is considered the major reinforcing component in tobacco smoke responsible for tobacco addiction. Nicotine acts in the brain through the neuronal nicotinic acetylcholine receptors (nAChRs). The predominant nAChR subtypes in mammalian brain are those containing α4 and β2 subunits. The α4β2 nAChRs, particularly those located in the mesoaccumbens dopamine pathway, play a key role in regulating the reinforcing properties of nicotine. Considering that twelve mammalian nAChR subunits have been cloned, it is likely that nAChRs containing subunits in addition to, or other than, α4 and β2 also play a role in the tobacco smoking habit. Consistent with this possibility, human genome-wide association studies have shown that genetic variation in the CHRNA5-CHRNA3-CHRNB4 gene cluster located in chromosome region 15q25, which encode the α5, α3 and β4 nAChR subunits, respectively, increases vulnerability to tobacco addiction and smoking-related diseases. Most recently, α5-containing nAChRs located in the habenulo-interpeduncular tract were shown to limit intravenous nicotine self-administration behavior in rats and mice, suggesting that deficits in α5-containing nAChR signaling in the habenulo-interpeduncular tract increases vulnerability to the motivational properties of nicotine. Finally, evidence suggests that nAChRs may also play a prominent role in controlling consumption of addictive drugs other than nicotine, including cocaine, alcohol, opiates and cannabinoids. The aim of the present review is to discuss recent preclinical findings concerning the identity of the nAChR subtypes that regulate self-administration of nicotine and other drugs of abuse.

Fig 1. Expression of nAChR subunits in brain regions relevant to nicotine reinforcement

Graphical representation of nAChR subtypes expressed in brain regions implicated in the rewarding and reinforcing properties of nicotine and other drugs of abuse. The red arrows indicate neuronal projections. There is dense expression of nAChR subtypes in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc) [, , –263], which are two major sites of ascending dopamine projections. Sites of dopaminergic input, including the nucleus accumbens (NAc), dorsal striatum, prefrontal cortex (PFC) and hippocampus [, , –266] are also enriched in nAChR subtypes. Other brain sites that have dense nAChR expression and that have been implicated in regulating nicotine self-administration behavior include the medial habenula and interpeduncular nucleus (IPN), and amygdala [260, 264, 267].