Neurotrophin-3 contributes to the initiation of behavioral sensitization to cocaine by activating the Ras/Mitogen-activated protein kinase signal transduction cascade

J Neurosci. 1999 Oct 1;19(19):8685-95. doi: 10.1523/JNEUROSCI.19-19-08685.1999.


These experiments were designed to assess the role of neurotrophins and the Ras/mitogen-activated protein kinase (MAP) signal transduction cascade in behavioral sensitization to cocaine. The first experiments evaluated the effect of three daily intra-ventral tegmental area (VTA) microinjections of neurotrophin-3 (NT-3) or brain-derived neurotrophic factor (BDNF) on the behavioral-activating effects of a subsequent challenge injection of cocaine in rats. Results indicated that, although NT-3 did not influence behavior across the three microinjection days, animals displayed a sensitized behavioral response to the subsequent cocaine challenge injection. In contrast, BDNF microinjections resulted in a progressive increase in behavioral activity but did not influence the subsequent behavioral response to cocaine. A second series of experiments assessed the effect of inhibiting the MAP kinase signal transduction cascade on the initiation of behavioral sensitization to cocaine. The MAP kinase kinase inhibitor PD98059, or its vehicle, was microinjected into the VTA before three daily cocaine injections. Although PD98059 did not influence the acute behavioral response to cocaine, it blocked sensitization. Finally, the effects of acute and repeated cocaine injections on NT-3 and BDNF mRNA levels in the VTA, substantia nigra, and hippocampus were assessed. Results indicated that an acute cocaine injection resulted in a transient increase in NT-3 mRNA levels in the VTA. Collectively, these results suggest that NT-3 contributes to the initiation of behavioral sensitization to cocaine by activating the Ras/MAP kinase signal transduction system. The present data also indicate that BDNF itself produced a progressive augmentation in behavioral activation with repeated administration.

Publication types

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

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cocaine / pharmacology*
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / administration & dosage
  • Flavonoids / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / physiology
  • Male
  • Microinjections
  • Mitogen-Activated Protein Kinase Kinases
  • Nerve Growth Factors / administration & dosage
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / pharmacology*
  • Neurotrophin 3
  • Protein Kinase Inhibitors
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects*
  • Stereotyped Behavior / drug effects*
  • Substance Withdrawal Syndrome
  • Substantia Nigra / drug effects
  • Substantia Nigra / physiology*
  • Tegmentum Mesencephali / drug effects
  • Tegmentum Mesencephali / physiology*
  • Transcription, Genetic / drug effects
  • ras Proteins / metabolism


  • Brain-Derived Neurotrophic Factor
  • Enzyme Inhibitors
  • Flavonoids
  • Nerve Growth Factors
  • Neurotrophin 3
  • Protein Kinase Inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • ras Proteins
  • Cocaine
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one