Brain gene expression in the context of nicotine rewards: A focus on cholinergic genes

Nicotine addiction is a significant public health liability that currently lacks effective treatments that promote long-term abstinence. Many clinical studies examining the genetic risk factors associated with nicotine dependence and smoking cessation outcomes have identified numerous polymorphisms in cholinergic genes, such as those clustered around the CHRNA5-CHRNA3-CHRNB4 gene locus. In addition, several preclinical studies have demonstrated a significant role of these cholinergic genes in mediating both the rewarding and aversive properties of nicotine. Polymorphisms within other neurotransmitter and neuromodulator systems have also been identified as significant contributors to nicotine dependence, though less is known about these targets. While tremendous progress has been made in identifying key gene variants associated with nicotine dependence, the literature remains considerably inconsistent. We recommend that future research investigate factors such as neuropsychiatric comorbidity and epigenetics to more precisely elucidate the specific contributions of gene variants in nicotine dependence and relapse vulnerability.