The roles of calcium/calmodulin-dependent and Ras/mitogen-activated protein kinases in the development of psychostimulant-induced behavioral sensitization

J Neurochem. 2003 Apr;85(1):14-22. doi: 10.1046/j.1471-4159.2003.01662.x.


Although the development of behavioral sensitization to psychostimulants such as cocaine and amphetamine is confined mainly to one nucleus in the brain, the ventral tegmental area (VTA), this process is nonetheless complex, involving a complicated interplay between neurotransmitters, neuropeptides and trophic factors. In the present review we present the hypothesis that calcium-stimulated second messengers, including the calcium/calmodulin-dependent protein kinases and the Ras/mitogen-activated protein kinases, represent the major biochemical pathways whereby converging extracellular signals are integrated and amplified, resulting in the biochemical and molecular changes in dopaminergic neurons in the VTA that represent the critical neuronal correlates of the development of behavioral sensitization to psychostimulants. Moreover, given the important role of calcium-stimulated second messengers in the expression of behavioral sensitization, these signal transduction systems may represent the biochemical substrate through which the transient neurochemical changes associated with the development of behavioral sensitization are translated into the persistent neurochemical, biochemical and molecular alterations in neuronal function that underlie the long-term expression of psychostimulant-induced behavioral sensitization.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Amphetamine / pharmacology
  • Animals
  • Behavior, Addictive / chemically induced*
  • Behavior, Addictive / metabolism
  • Calcium / metabolism
  • Calcium Channels, L-Type / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology*
  • Central Nervous System Stimulants / pharmacology*
  • Cocaine / pharmacology
  • Dopamine / metabolism
  • Dopamine Uptake Inhibitors / pharmacology
  • Glutamic Acid / metabolism
  • Humans
  • Mitogen-Activated Protein Kinases / metabolism
  • Mitogen-Activated Protein Kinases / physiology*
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / physiology
  • Second Messenger Systems / physiology
  • Synaptic Transmission / drug effects
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism
  • ras Proteins / metabolism*


  • Calcium Channels, L-Type
  • Central Nervous System Stimulants
  • Dopamine Uptake Inhibitors
  • Glutamic Acid
  • Amphetamine
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • ras Proteins
  • Cocaine
  • Calcium
  • Dopamine