The nicotinic cholinergic receptor contains five subunits. In the mammalian brain there are 9 alpha subunits (alpha 2 through alpha 10), and 3 beta subunits (beta 2 through beta 4). Although there are a large number of possible combinations a limited number of subtypes appear to account for most biologic effects. The alpha 4 beta 2* (*other subunits may be present) appears to be the principle mediator of nicotine dependence since disruption of the beta 2 subunit gene reduces the behavior effects of nicotine and reinsertion of the gene into the ventral tegmental area (VTA) containing dopaminergic cells restores it. A mutation in the alpha 4 gene can increase sensitivity to nicotine. The combination of a alpha 5 subunit with alpha 4 beta 2 subunits increases calcium conductance and a genetic variation in the alpha 5 gene interact with childhood adversity to increase smoking. The alpha 7-homomeric receptors regulate rapid glutamatergic transmission into the VTA, which can alter long-term potentiation in dopamine neurons. The alpha 3 beta 4 receptor is thought to mediate the cardiovascular effects of nicotine. Thus there are many factors at the nicotinic receptor subunit level that can alter the response to nicotine.