Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization

Nat Neurosci. 2011 Jan;14(1):22-4. doi: 10.1038/nn.2703. Epub 2010 Dec 5.


Dorsal striatum is important for the development of drug addiction; however, a precise understanding of the roles of striatopallidal (indirect) and striatonigral (direct) pathway neurons in regulating behaviors remains elusive. Using viral-mediated expression of an engineered G protein-coupled receptor (hM(4)D), we found that activation of hM(4)D receptors with clozapine-N-oxide (CNO) potently reduced striatal neuron excitability. When hM(4)D receptors were selectively expressed in either direct or indirect pathway neurons, CNO did not change acute locomotor responses to amphetamine, but did alter behavioral plasticity associated with repeated drug treatment. Specifically, transiently disrupting striatopallidal neuronal activity facilitated behavioral sensitization, whereas decreasing excitability of striatonigral neurons impaired its persistence. These findings suggest that acute drug effects can be parsed from the behavioral adaptations associated with repeated drug exposure and highlight the utility of this approach for deconstructing neuronal pathway contributions to behavior.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphetamine / pharmacology
  • Animals
  • Cell Line, Transformed
  • Clozapine / analogs & derivatives
  • Clozapine / pharmacology
  • Corpus Striatum / drug effects
  • Corpus Striatum / physiology*
  • Dopamine / metabolism
  • Genetic Vectors
  • Herpes Simplex / genetics
  • Humans
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Neural Inhibition / drug effects
  • Neural Inhibition / genetics
  • Neural Inhibition / physiology*
  • Neural Pathways / drug effects
  • Neural Pathways / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Muscarinic M4 / agonists
  • Receptor, Muscarinic M4 / genetics
  • Receptor, Muscarinic M4 / physiology*
  • Reward
  • Ventral Tegmental Area / metabolism
  • Ventral Tegmental Area / physiology


  • Receptor, Muscarinic M4
  • Amphetamine
  • Clozapine
  • clozapine N-oxide
  • Dopamine