Supporting possible relevance to CD, many lines of evidence show that CB1 and its ligands are involved in the regulation of mesocorticolimbic dopamine (DA) reward pathways that project from VTA to nucleus accumbens (NAc), prefrontal cortex (PFC), amygdala and hippocampus. The mesocorticolimbic DA reward pathways are the main hypothesized pathways for addiction, including CD (Di Chiara and Imperato 1988; Koob 1992; Koob and Le Moal 2001; Koob and Le Moal 2008; Lupica and Riegel 2005; Nestler 2005; Tanda and Goldberg 2003). Although all classes of commonly abused substances activate the mesocorticolimbic system, the mechanisms of this activation differs across abusable substances. In contrast to opioids, nicotine, or alcohol, the main receptor for cocaine is the DA transporter, to which cocaine binds, resulting in the suppression of DA reuptake, with a subsequent increase in extracellular DA level (Hyman et al 2006). Some studies suggested that CB1 might not play a critical role in cocaine self-administration (Caille et al 2007; Cossu et al 2001), but the role of the DA system on the effects of cocaine and the modulatory role of the endocannibinoid system in DA reward pathways suggest that CB1 may be involved in the risk of developing CD.
