Reducing Ventral Tegmental Dopamine D2 Receptor Expression Selectively Boosts Incentive Motivation

Neuropsychopharmacology. 2015 Aug;40(9):2085-95. doi: 10.1038/npp.2015.60. Epub 2015 Mar 4.


Altered mesolimbic dopamine signaling has been widely implicated in addictive behavior. For the most part, this work has focused on dopamine within the striatum, but there is emerging evidence for a role of the auto-inhibitory, somatodendritic dopamine D2 receptor (D2R) in the ventral tegmental area (VTA) in addiction. Thus, decreased midbrain D2R expression has been implicated in addiction in humans. Moreover, knockout of the gene encoding the D2R receptor (Drd2) in dopamine neurons has been shown to enhance the locomotor response to cocaine in mice. Therefore, we here tested the hypothesis that decreasing D2R expression in the VTA of adult rats, using shRNA knockdown, promotes addiction-like behavior in rats responding for cocaine or palatable food. Rats with decreased VTA D2R expression showed markedly increased motivation for both sucrose and cocaine under a progressive ratio schedule of reinforcement, but the acquisition or maintenance of cocaine self-administration were not affected. They also displayed enhanced cocaine-induced locomotor activity, but no change in basal locomotion. This robust increase in incentive motivation was behaviorally specific, as we did not observe any differences in fixed ratio responding, extinction responding, reinstatement or conditioned suppression of cocaine, and sucrose seeking. We conclude that VTA D2R knockdown results in increased incentive motivation, but does not directly promote other aspects of addiction-like behavior.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cocaine / administration & dosage
  • Conditioning, Operant / drug effects
  • Conditioning, Operant / physiology
  • Dopamine Uptake Inhibitors / administration & dosage
  • Extinction, Psychological / drug effects
  • Gene Expression Regulation / physiology*
  • HEK293 Cells
  • Humans
  • Male
  • Motivation / physiology*
  • Motor Activity / drug effects
  • RNA, Small Interfering / metabolism
  • RNA, Small Interfering / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Dopamine D2 / genetics*
  • Receptors, Dopamine D2 / metabolism*
  • Self Administration
  • Sucrose / administration & dosage
  • Sweetening Agents / administration & dosage
  • Tyrosine 3-Monooxygenase / metabolism
  • Ventral Tegmental Area / metabolism*


  • Dopamine Uptake Inhibitors
  • RNA, Small Interfering
  • Receptors, Dopamine D2
  • Sweetening Agents
  • Sucrose
  • Tyrosine 3-Monooxygenase
  • Cocaine