Addictive drugs mediate their reinforcing properties by targeting the mesocorticolimbic dopamine (DA) system, which we define as including the ventral tegmental area (VTA) and its major targets, the nucleus accumbens (NAc) and prefrontal cortex (PFC). Despite their chemical diversity and individual molecular targets, all addictive drugs have in common that they increase DA concentrations in projection areas of the VTA as well as the VTA itself (Di Chiara and Imperato, 1988; Nestler, 2005). In brief (for a more extensive review on the pharmacology of addictive drugs see review by D. Sulzer in the present issue of Neuron and (Lüscher and Ungless, 2006), nicotine can directly increase firing of DA neurons through α4β2 containing nicotinic receptors that are expressed on DA neurons (Maskos et al., 2005). Opioids (Johnson and North, 1992), cannabinoids (Szabo et al., 2002), the club-drugγ-hydoxybutyrate (GHB) (Cruz et al., 2004) and benzodiazepines (Tan et al., 2010) primarily target GABAergic interneurons in the VTA and decrease their activity, which leads to an indirect increase of DA neuron activity. Such disinhibition can occur because of the cell-type specific expression of
