These initial actions of addictive drugs have been extensively studied and remain important targets for possible therapeutic interventions in the treatment of addiction1 (Fig. 1). For example, the drug varenicline, which is used in the treatment of nicotine addiction, targets nicotinic receptors on VTA DA neurons (Coe et al., 2005). However, the acute actions of drugs of abuse dissipate as the drug leaves the brain and therefore, alone, cannot explain the development of addictive behaviors. To understand addiction we must elucidate the specific traces the drug experience leaves in the brain and which of these are causally related to the development of addiction. Here, we will focus on some of the key synaptic adaptations that occur after single or repetitive exposures to an addictive drug. This focus is based on the assumption that like virtually all forms of adaptive experience-dependent plasticity, the neural circuit adaptations that underlie drug-induced behavioral changes will involve drug-induced synaptic changes. Indeed, converging evidence from many studies suggests that addictive drugs modify synaptic transmission in the mesocorticolimbic DA system by hijacking mechanisms normally used for adaptive
