Loss of cocaine locomotor response in Pitx3-deficient mice lacking a nigrostriatal pathway

Neuropsychopharmacology. 2009 Apr;34(5):1149-61. doi: 10.1038/npp.2008.117. Epub 2008 Aug 13.


Both the dorsal and ventral striatum have been demonstrated to have a critical role in reinforcement learning and addiction. Dissecting the specific function of these striatal compartments and their associated nigrostriatal and mesoaccumbens dopamine pathways, however, has proved difficult. Previous studies using lesions to isolate the contribution of nigrostriatal and mesoaccumbens dopamine in mediating the locomotor and reinforcing effects of psychostimulant drugs have yielded inconsistent and inconclusive results. Using a naturally occurring mutant mouse line, aphakia, that lacks a nigrostriatal dopamine pathway but retains an intact mesoaccumbens pathway, we show that the locomotor activating effects of cocaine, including locomotor sensitization, are dependent on an intact nigrostriatal dopamine projection. In contrast, cocaine reinforcement, as measured by conditioned place preference and cocaine sensitization of sucrose preference, is intact in these mice. In light of the well-established role of the nucleus accumbens in mediating the effects of psychostimulants, these data suggest that the nigrostriatal pathway can act as a critical effector mechanism for the nucleus accumbens highlighting the importance of intrastriatal connectivity and providing insight into the functional architecture of the striatum.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • Central Nervous System Stimulants / toxicity
  • Cocaine / toxicity*
  • Conditioning, Psychological / physiology
  • Corpus Striatum / physiology*
  • Dopamine / metabolism
  • Dose-Response Relationship, Drug
  • Homeodomain Proteins / genetics
  • Immunohistochemistry
  • Mice
  • Mice, Mutant Strains
  • Motor Activity / drug effects*
  • Neural Pathways / physiology*
  • Neurons / metabolism
  • Regression Analysis
  • Reinforcement, Psychology
  • Space Perception / drug effects
  • Substantia Nigra / physiopathology*
  • Transcription Factors / genetics
  • Tyrosine 3-Monooxygenase / metabolism


  • Central Nervous System Stimulants
  • Homeodomain Proteins
  • Transcription Factors
  • homeobox protein PITX3
  • Tyrosine 3-Monooxygenase
  • Cocaine
  • Dopamine