A Role for the Extracellular Signal-regulated Kinase Signal Pathway in Depressive-like Behavior

Our recent research demonstrates that the extracellular signal-regulated kinase (ERK) signal pathway is impaired in depressed animals, and such disruption is effectively reversed following antidepressant treatment. These results indicate that the ERK pathway may participate in the molecular mechanism of depression. To provide direct evidence for the potential role of the ERK pathway in depression, the present study using a sub-chronic regimen of ERK inhibition investigated the disparate role for the ERK cascade in two specific brain areas, the dorsal hippocampus (dHP) and the medial prefrontal cortex (mPFC), in the pathophysiology of depressive-like behavior. Rats were bilaterally implanted with cannulas in the dHP or mPFC and were microinjected with U0126, a specific inhibitor of ERK upstream activator, or vehicle for 7 consecutive days. The behavioral effects of the ERK pathway inhibition were examined in the open field, elevated plus maze, and saccharin preference test. The results showed that the inhibition of the ERK pathway in dHP resulted in anhedonia and anxiety-like behavior, and the ERK pathway inhibition in the mPFC induced anhedonia and locomotor impairment in rats. The phosphorylation of the cyclic AMP-responsive-element-binding protein (CREB) was decreased following the ERK pathway inhibition either in dHP or mPFC. These findings demonstrate that the ERK pathway in either the dHP or mPFC participates in the pathophysiology of the depressive-like behavior, and may have pivotal role in human depression.