1 When the drug was removed, the enzyme's activity spiked, which the authors interpret as a cellular withdrawal from dependency: "This phenomenon can be likened to the abstinence syndrome in animals."
It wasn't until more than a decade later, in the early 1990s, when Nestler, then at Yale University, and his group replicated the results in vivo and moved two steps downstream from adenylyl cyclase to the activation of CREB. They showed that a dose of morphine impairs the phosphorylation of CREB (a marker of CREB activation), but that activity returns to normal after a longer exposure to the drug.2 "Around the same time," Nestler recalls, "we were asking: The locus ceruleus is just a model system for the opiate system, but do other neurons respond?" He turned to the nucleus accumbens, a group of neurons that receive dopaminergic inputs from the ventral tegmental area, and which ...
