Dopamine signaling in brain reward areas is a key element in the development of drug abuse and dependence. Recent anatomical and electrophysiological research has begun to elucidate both complexity and specificity in synaptic connections between ventral tegmental neurons and their inputs. Specifically, the activity of dopamine neurons in the ventral tegmental area relies on the combination of both excitatory and inhibitory inputs. Controlling endogenous neurotransmission to dopamine neurons is one mechanism by which drugs of abuse affect both transient and long-term changes in synaptic activity. Here, we review recent findings concerning glutamatergic, GABAergic, and cholinergic inputs to dopamine neurons, and their roles in the reinforcement associated with drug abuse. Importantly, several studies support that a single drug exposure can lead to changes in synaptic strength that are associated with learning and memory. Ultimately, these cellular changes could underlie the long-lasting effects of drugs. Furthermore, nicotinic acetylcholine receptors in the ventral tegmental area emerge as a possible common target for the behavioral and cellular actions not only of nicotine, but also of several other drugs of abuse. Finally, we explore age-related differences in nicotine sensitivity in order to understand both human epidemiological data, and laboratory animal behavioral findings that suggest adolescents are more susceptible to developing nicotine dependence.