The results outlined in the previous sections strongly argue for the involvement of the EC system in regulating aspects of the acute response to ethanol, the establishment of tolerance/dependence, and the propensity to relapse. In this section we will briefly summarize the salient points mentioned earlier and provide a tentative model for the change in function of the EC system across these stages of addiction (figure 2). To begin, a consistent finding has been that ethanol interacts with the EC system to produce its acute, reinforcing effects which may drive further drug seeking. Studies of VTA DA neuron activity and of DA concentrations in the NAc provide support for the hypothesis that ethanol-induced EC release in the VTA serves to activate DA neurons (Cheer et al., 2004; Cheer et al., 2007; Hungund et al., 2003; Perra et al., 2005). One mechanism that likely contributes to this effect is a disinhibition of DA neurons produced by a CB1-mediated decrease of GABA release onto these neurons (Riegel and Lupica, 2004). In addition, acute ethanol inhibits hippocampal neurons via an EC-mediated reduction in
