REGULATION OF ERK (EXTRACELLULAR SIGNAL-REGULATED KINASE), PART OF THE NEUROTROPHIN SIGNAL-TRANSDUCTION CASCADE, IN THE RAT MESOLIMBIC DOPAMINE SYSTEM BY CHRONIC EXPOSURE TO MORPHINE OR COCAINE

Local infusion of brain-derived neurotrophic factor (BDNF) into the ve ntral tegmental area (VTA) can prevent and reverse the ability of chro nic morphine or cocaine exposure to induce tyrosine hydroxylase (TH) i n this brain region, The present study examined a possible role for ex tracellular signal regulated kinases (ERKs), the major effector for BD NF and related neurotrophins, in morphine and cocaine action in the VT A. Chronic, but not acute, administration of morphine or cocaine incre ased ERK catalytic activity specifically in the VTA. This increase in ERK activity reflected an increase in the state of phosphorylation of ERK, with no change in levels of total ERK immunoreactivity. Chronic i nfusions of BDNF into the VTA reduced total ERK immunoreactivity with no change in ERK activity, and also blocked the morphine-induced incre ase in ERK activity. These results suggest that chronic BDNF elicits a compensatory increase in the phosphorylation of the remaining ERK mol ecules and thereby prevents any additional increase in response to dru g exposure. Such a role for ERK in morphine action was demonstrated di rectly by chronically infusing antisense oligonucleotides to ERK1 into the VTA, This treatment selectively reduced levels of ERK1 immunoreac tivity in a sequence-specific manner without detectable toxicity. Intr a-VTA infusion of ERK1 antisense oligonucleotides mimicked the effects of chronic BDNF infusions on ERK immunoreactivity, ERK activity, and TH immunoreactivity in the VTA under both control and morphine-treated conditions. The chronic morphine-induced increases in ERK activity an d TH expression in the VTA also were blocked by local infusion of NMDA glutamate receptor antagonists, suggesting a role for glutamate in me diating these drug effects. Together, these findings support a scheme whereby chronic, systemic administration of morphine or cocaine leads to a sustained increase in ERK phosphorylation state and activity in t he VTA, which, in turn, contributes to drug-induced increases in TH, a nd perhaps other drug-induced adaptations, elicited selectively in thi s brain region.