Given these generalizations, it might seem beneficial to develop inhibitors of ERK, PKA, CaMKII, and PKCε to treat addiction. For PKCε this may be a reasonable approach since PKCε knockout mice are viable and show few phenotypes that raise the specter of serious side effects resulting from use of a PKCε inhibitor. However, ERK, CaMKII, and PKA are multifunctional kinases and the likelihood of inhibitors producing serious side effects is high. An alternative to modulating these kinases directly is to manipulate the signaling pathways in which they function. One approach is to develop drugs that regulate upstream activators or downstream effectors of these kinases. For example, A2a receptors activate PKA, and A2a antagonists decrease alcohol consumption in some models.279 Likewise NPY, whose expression is increased by PKA, diminishes alcohol consumption when overexpressed in transgenic mice.280 Since NPY-Y2 receptors act as autoreceptors that decrease NPY release, the use of NPY-Y2 antagonists has been explored as a strategy to reduce drinking in rodents. In rats the NPY-Y2 antagonist BIIE0246 reduces alcohol consumption, especially in animals with a history of ethanol dependence resulting from exposure to ethanol vapor.281
