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Volume 16, Number 15,
Issue of August 1, 1996
pp. 4707-4715
Copyright ©1996 Society for Neuroscience
Regulation of ERK ( xtracellular Signal
 egulated  inase), Part of the Neurotrophin
Signal Transduction Cascade, in the Rat Mesolimbic Dopamine System
by Chronic Exposure to Morphine or Cocaine
Received March 26, 1996; revised May 6, 1996; accepted May 9, 1996.
Melissa T. Berhow,
Noboru Hiroi, and
Eric J. Nestler
Laboratory of Molecular Psychiatry, Departments of Psychiatry and
Pharmacology, Yale University School of Medicine, Connecticut Mental
Health Center, New Haven, Connecticut 06508
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
demonstrated 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.
Key words:
morphine;
cocaine;
antisense oligonucleotides;
ERK;
ventral tegmental area;
tyrosine hydroxylase;
BDNF;
NMDA glutamate
receptors
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