ERKs are serine-threonine protein kinases that are members of the mitogen-activated protein kinase (MAPK) family. Two isoforms have been identified, p44 ERK1 and p42 ERK2, which share similar, though not identical, functions. ERKs are involved in many aspects of neuronal function including control of cell growth, cell differentiation, neuronal survival, and synaptic plasticity.8–10 ERK1 and ERK2 are widely expressed throughout the brain, including in the mesolimbic dopaminergic system. Both are strongly expressed in the amygdala and prefrontal cortex and moderately expressed in the ventral tegmental area (VTA), nucleus accumbens (NAc), and midbrain.6 ERKs are activated by a Ras-Raf-MEK signaling cascade that involves sequential phosphorylation of upstream kinases. Several growth factors such as the brain-derived neurotrophic factor (BDNF) activate receptor tyrosine kinases that recruit the adapter proteins Grb2 and Shc, in turn leading to activation of the GTPase Ras. Ras can also be activated by calcium influx through L-type calcium channels or NMDA receptors through stimulation of Ras protein-specific guanine-nucleotide releasing factor (Ras-GRF1), a Ca2+-activated guanine nucleotide exchange factor expressed in neurons of the central nervous system.11 Ca2+ influx can be
