Role of the ERK pathway in psychostimulant-induced locomotor sensitization

BMC Neurosci. 2006 Mar 2;7:20. doi: 10.1186/1471-2202-7-20.

Abstract

Background: Repeated exposure to psychostimulants results in a progressive and long-lasting facilitation of the locomotor response that is thought to have implications for addiction. Psychostimulants and other drugs of abuse activate in specific brain areas extracellular signal-regulated kinase (ERK), an essential component of a signaling pathway involved in synaptic plasticity and long-term effects of drugs of abuse. Here we have investigated the role of ERK activation in the behavioral sensitization induced by repeated administration of psychostimulants in mice, using SL327, a brain-penetrating selective inhibitor of MAP-kinase/ERK kinase (MEK), the enzyme that selectively activates ERK.

Results: A dose of SL327 (30 mg/kg) that reduced the number of activated ERK-positive neurons by 62 to 89% in various brain areas, had virtually no effect on the spontaneous locomotor activity or the acute hyperlocomotion induced by cocaine or D-amphetamine. Pre-treatment with SL327 (30 mg/kg) prior to each drug administration prevented the locomotor sensitization induced by repeated injections of D-amphetamine or cocaine. The SL327 pre-treatment abolished also conditioned locomotor response of mice placed in the context previously paired with cocaine or D-amphetamine. In contrast, SL327 did not alter the expression of sensitized response to D-amphetamine or cocaine.

Conclusion: Altogether these results show that ERK has a minor contribution to the acute locomotor effects of psychostimulants or to the expression of sensitized responses, whereas it is crucial for the acquisition of locomotor sensitization and psychostimulant-conditioned locomotor response. This study supports the important role of the ERK pathway in long-lasting behavioral alterations induced by drugs of abuse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoacetonitrile / analogs & derivatives
  • Aminoacetonitrile / pharmacology
  • Animals
  • Behavior, Animal / drug effects
  • Brain / drug effects
  • Brain / enzymology*
  • Cocaine / pharmacology*
  • Conditioning, Psychological / drug effects
  • Dextroamphetamine / pharmacology*
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Extracellular Signal-Regulated MAP Kinases / physiology*
  • MAP Kinase Signaling System / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity / drug effects*
  • Phosphorylation / drug effects
  • Psychotropic Drugs / pharmacology*

Substances

  • Enzyme Inhibitors
  • Psychotropic Drugs
  • SL 327
  • Aminoacetonitrile
  • Extracellular Signal-Regulated MAP Kinases
  • Cocaine
  • Dextroamphetamine