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

Abstract

Local infusion of brain-derived neurotrophic factor (BDNF) into the ventral tegmental area (VTA) can prevent and reverse the ability of chronic morphine or cocaine exposure to induce tyrosine hydroxylase (TH) in this brain region. The present study examined a possible role for extracellular signal regulated kinases (ERKs), the major effector for BDNF and related neurotrophins, in morphine and cocaine action in the VTA. Chronic, but not acute, administration of morphine or cocaine increased 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 infusions of BDNF into the VTA reduced total ERK immunoreactivity with no change in ERK activity, and also blocked the morphine-induced increase in ERK activity. These results suggest that chronic BDNF elicits a compensatory increase in the phosphorylation of the remaining ERK molecules and thereby prevents any additional increase in response to drug exposure. Such a role for ERK in morphine action was demnostrated directly by chronically infusing antisense oligonucleotides to ERK1 into the VTA. This treatment selectively reduced levels of ERK1 immunoreactivity in a sequence-specific manner without detectable toxicity. Intra-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 and TH expression in the VTA also were blocked by local infusion of NMDA glutamate receptor antagonists, suggesting a role for glutamate in mediating 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 the VTA, which, in turn, contributes to drug-induced increases in TH, and perhaps other drug-induced adaptations, elicited selectively in this brain region.

Striatal Dopaminergic and Serotonergic Markers in Human Heroin Users

“…Animal data suggest that ERK might be involved in regulation by opiate drugs of tyrosine hydroxylase, with protein levels increased in rat "striatum" (the rodent counterpart of the human caudate and putamen) following chronic morphine administration (Ortiz et al 1995;Berhow et al 1996). Our data suggest, however, that any regulation by ERK of tyrosine hydroxylase in the human does not involve changes in actual striatal levels of ERK.…”

“…Wakabayashi et al 1995, we measured levels of dopamine metabolites (homovanillic acid, 3-methoxytyramine, dihdroxyphenylacetic acid), serotonin and metabolite 5-hydroxyindoleacetic acid, and noradrenaline. Finally, as experimental animal data show that chronic opiate administration can upregulate striatal concentrations of extracellular signal-regulated kinases (ERKs), signaling molecules that may be involved in the regulation of levels of tyrosine hydroxylase (Ortiz et al 1995;Berhow et al 1996), we also determined striatal concentration of ERK2 in the heroin users. Our biochemical findings suggest that chronic heroin exposure might modestly decrease both dopaminergic and serotonergic function in the human.…”

Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

“…No changes in total ERK and CREB were observed at any dose and no changes in P-ERK or P-CREB were observed in animals of either genotype treated with 0.25 mg/kg morphine (not shown). Since inhibition of ERK1/2 phosphorylation in the VTA blocks the rewarding effects of morphine (Berhow et al, 1996;Ozaki et al, 2004), the observed increases in ERK1/2 activation may regulate (a) Galanin wild-type (WT; n ¼ 10) and knockout (GKO; n ¼ 11) mice were administered an acute i.p. injection of saline followed by 0, 5, 10, or 20 mg/kg morphine 15 min later.…”

“…These studies further examined whether second messenger signaling pathways that support these morphine-regulated behaviors are modulated by galanin. At the molecular level, morphine administration leads to enhanced phosphorylation, and thus activation of extracellularregulated kinase (ERK1/2) in the VTA, hippocampus, NAc, cingulate cortex, and amygdala (Berhow et al, 1996;Valjent et al, 2004). Increased ERK1/2 phosphorylation in the VTA is associated with morphine and psychostimulant reward (Ozaki et al, 2004) and systemic inhibition of ERK1/2 phosphorylation blocks expression of morphine and cocaine CPP (Valjent et al, 2006a).…”

Nucleotide sequence variation within the human tyrosine kinase B neurotrophin receptor gene: association with antisocial alcohol dependence

“…This concept was supported by a previous report using rats that received an infusion of BDNF into the ventral tegmental area, preventing drug-induced adaptations in a brain region known to be involved in drug reinforcing behavior. 20 The essential functional role of BDNF in TrkB-mediated signaling was demonstrated in a model of neurodegeneration, where survival of hippocampal neurons in culture derived from trisomy 16 mice, which produce the truncated kinasedeficient isoform, Trk-T1, and would be destined to die were restored by introduction of exogenous full-length TrkB. 21 A role for TrkB linked to AD in humans has not been reported.…”