Chronic exposure to cocaine increases the activity of extracellular signal-regulated kinase (ERK1/2) in the ventral tegmental area (VTA), a neural substrate for drugs of abuse. However, the functional significance of changes in ERK1/2 activity in this brain region is unknown. Using herpes simplex virus-mediated gene transfer to regulate ERK2 activity within the VTA in male rats, we show that overexpressing ERK2 increases preference for environments previously paired with low doses of cocaine and enhances cocaine-induced locomotion, whereas blocking ERK2 activity blocks cocaine-induced place conditioning and locomotor activity. These results demonstrate that ERK2-signaling within the VTA is a key modulator of functional responses to cocaine.
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