Administration of addictive drugs to rats and mice can activate ERK in many of the brain regions that constitute or are targets of the mesolimbic dopaminergic system, including the VTA, NAc, prefrontal cortex, bed nucleus of the stria terminalis (BNST), and the amygdala.14,15 ERK activation can be measured as a drug-induced increase in phosphorylated ERK protein (p-ERK) that can be blocked by selective MEK inhibitors, such as U0126, SL327, or PD98059, which prevent ERK activation. Acute cocaine treatment transiently increases p-ERK throughout the striatum through a mechanism that involves activation of D1 dopamine and NMDA receptors. This increase in p-ERK can be blocked by systemic injection of SL327.16,17 SL327 also inhibits cocaine-induced c-fos expression and Elk-1 hyperphosphorylation. Acute and repeated administration of cocaine also increases p-ERK in the prefrontal cortex, BNST, and amygdala. In the VTA, cocaine increases levels of p-ERK, but only after repeated administration.18
