Appetitive, approach-promoting mechanisms are critical for the initiation phase of addiction. As addiction develops, negative emotional states triggered by stress and withdrawal promote negatively reinforced drug seeking and taking, through activity of systems that encode aversive emotional states, and that have evolved to motivate behavioral avoidance. Up-regulated CRF / CRF1R function within the amygdala is a key factor behind this negatively reinforced drug seeking and taking (Heilig and Koob, 2007; Koob and Zorrilla, 2010). Within the amygdala, CRF and NPY oppositely influence cental amygdala output following stress exposure (Gilpin and Roberto, 2012; Heilig et al., 1994). Stress modulators other than CRF and NPY are likely to act upstream of the cental amygdala circuitry, or interact with it to drive negatively reinforced drug seeking. The precise organization of these systems has for the most part not been studied directly, and even the limited data available are inconclusive. Clearly, we are only at the beginning of understanding the interactions within these complex networks.
