Nicotinic acetylcholine receptors (nAChR) are expressed in multiple types of neurons, and have been shown to modulate reward response for several substances5. For example, work in animals suggests that activation of α3β4 nAChR can increase cocaine self-administration31. Because comorbidity between substance dependencies is so high, it is plausible that these receptors could play a role in addiction to multiple substances. Most drugs of abuse act on the mesolimbic dopamine-containing receptors in the brains of humans and many other mammals. Among other functions, this system is known to regulate motivation3233 and has similar effects across mammalian species34. Activation and reinforcement of this system is a necessary part of drug abuse32. The dopaminergic system is therefore crucial to addiction, however other neurotransmitters besides dopamine affect the mesolimbic system, especially acetylcholine31. The biological connection between these two systems could be related to the reversal of the odds ratio for rs16969968, which is protective for cocaine dependence but a risk factor for nicotine dependence, as well as our observation that in the CHRNB3-A6 locus on chromosome 8, there are variants associated with protection against
