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Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors.

Dopamine (DA) D2 receptors expressed in DA neurons (D2 autoreceptors) exert a negative feedback regulation that reduces DA neuron firing, DA synthesis and DA release. As D2 receptors are mostly expressed in postsynaptic neurons, pharmacological and genetic approaches have been unable to definitively address the in vivo contribution of D2 autoreceptors to DA-mediated behaviors. We found that midbrain DA neurons from mice deficient in D2 autoreceptors (Drd2(loxP/loxP); Dat(+/IRES-cre), referred to as autoDrd2KO mice) lacked DA-mediated somatodendritic synaptic responses and inhibition of DA release. AutoDrd2KO mice displayed elevated DA synthesis and release, hyperlocomotion and supersensitivity to the psychomotor effects of cocaine. The mice also exhibited increased place preference for cocaine and enhanced motivation for food reward. Our results highlight the importance of D2 autoreceptors in the regulation of DA neurotransmission and demonstrate that D2 autoreceptors are important for normal motor function, food-seeking behavior, and sensitivity to the locomotor and rewarding properties of cocaine.

Pubmed ID: 21743470


  • Bello EP
  • Mateo Y
  • Gelman DM
  • NoaĆ­n D
  • Shin JH
  • Low MJ
  • Alvarez VA
  • Lovinger DM
  • Rubinstein M


Nature neuroscience

Publication Data

August 27, 2011

Associated Grants

  • Agency: NIMH NIH HHS, Id: R01-MH61326
  • Agency: Intramural NIH HHS, Id: ZIA AA000416-04
  • Agency: Intramural NIH HHS, Id: ZIA AA000421-02
  • Agency: Intramural NIH HHS, Id: ZIA AA000421-03
  • Agency: Intramural NIH HHS, Id: ZIA AA000421-04

Mesh Terms

  • Analysis of Variance
  • Animals
  • Autoradiography
  • Baclofen
  • Choice Behavior
  • Cocaine
  • Conditioning, Operant
  • Dihydroxyphenylalanine
  • Dopamine
  • Dopamine Agonists
  • Dopamine Antagonists
  • Dopamine Uptake Inhibitors
  • Drug Interactions
  • Enzyme Inhibitors
  • Exploratory Behavior
  • Food
  • GABA-B Receptor Agonists
  • Hydrazines
  • Hyperkinesis
  • In Vitro Techniques
  • Maze Learning
  • Membrane Potentials
  • Mesencephalon
  • Mice
  • Mice, Knockout
  • Motivation
  • Motor Activity
  • Neurons
  • Quinpirole
  • Receptors, Dopamine D2
  • Reinforcement Schedule
  • Reward
  • Sulpiride