Netrin-1 receptor in the ventral tegmental area is required for sensitization to amphetamine

Eur J Neurosci. 2010 Apr;31(7):1292-302. doi: 10.1111/j.1460-9568.2010.07163.x. Epub 2010 Mar 19.


Fundamental to neural organization during development, the netrin-1 guidance cue and its receptor, deleted in colorectal cancer (DCC), continue to be expressed in the adult brain. We have shown recently that adult dcc heterozygous mice do not develop sensitization to the stimulant drug of abuse amphetamine (AMPH) and that repeated exposure to AMPH upregulates DCC expression in adult rats. This upregulation is selective to the ventral tegmental area (VTA), a site critical for the initiation of behavioral plasticity induced by stimulant drugs, and is glutamate-dependent. Here we demonstrate that the lack of AMPH-induced sensitization in dcc heterozygotes is associated with a failure of AMPH to upregulate DCC receptor expression in the VTA. Further, we show that, in wild-type mice, repeated AMPH induces increases in VTA expression of the dendritic spine-associated protein, spinophilin. Significantly, however, this effect is not observed in dcc heterozygotes. In parallel experiments conducted in adult rats, we show that VTA DCC receptor activation, at the time of AMPH pretreatment, is critical for sensitization to AMPH. Together, these results demonstrate that the DCC netrin-1 receptor, a protein traditionally known for its role in organizing brain development, plays a critical function in adult brain plasticity, possibly via orchestration of neuronal circuitry reorganization. We propose VTA DCC receptor signaling as a novel mechanism in the series of glutamate-dependent cellular processes that lead to enduring plasticity by drugs of abuse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphetamine / pharmacology*
  • Animals
  • Animals, Newborn
  • Behavior, Animal / drug effects
  • Central Nervous System Stimulants / pharmacology*
  • DCC Receptor
  • Male
  • Mice
  • Mice, Knockout
  • Microfilament Proteins / metabolism
  • Nerve Growth Factors / deficiency
  • Nerve Growth Factors / metabolism*
  • Nerve Tissue Proteins / metabolism
  • Netrin Receptors
  • Netrin-1
  • Rats
  • Rats, Wistar
  • Receptors, Cell Surface / deficiency
  • Receptors, Cell Surface / metabolism
  • Time Factors
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / metabolism*
  • Up-Regulation / drug effects*
  • Up-Regulation / genetics
  • Ventral Tegmental Area / drug effects*
  • Ventral Tegmental Area / metabolism*


  • Central Nervous System Stimulants
  • DCC Receptor
  • Dcc protein, mouse
  • Microfilament Proteins
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Netrin Receptors
  • Ntn1 protein, mouse
  • Ntn1 protein, rat
  • Receptors, Cell Surface
  • Tumor Suppressor Proteins
  • neurabin
  • Netrin-1
  • Amphetamine