Although CREB is predominantly thought of in relation to PKA-mediated signaling, extracellular signal-regulated kinase (ERK) preferentially activates CREB following repeated exposure to cocaine (Lu et al., 2005). ERK can act directly on AMPARs to increase AMPAR surface insertion, which is required for expression of NMDA-dependent LTP (Zhu et al., 2002). Furthermore, cocaine-induced striatal ERK activation is PKA- and DARPP-32-dependent, and ERK inhibition attenuated cocaine-induced conditioned place preference and behavioral sensitization (Valjent et al., 2005). Moreover, ERK in the central amygdala was shown to be both necessary and sufficient for the incubation of cocaine craving (Lu et al., 2005). While ERK acting directly on AMPA or through ΔFosB could facilitate the AMPAR role in psychostimulant reinforcement, further work is needed to define the relationship between ERK and AMPARs, and this remains an interesting area of investigation.
