Retinoid x receptor gamma control of affective behaviors involves dopaminergic signaling in mice

Neuron. 2010 Jun 24;66(6):908-20. doi: 10.1016/j.neuron.2010.05.004.


Abnormal signaling by retinoids or n-3 polyunsaturated fatty acids has been implicated in clinical depression. The converging point in activities of these two classes of molecules is transcriptional activation of retinoid X receptors (Rxr). We show here that ablation of Rxrgamma in mice leads to depressive-like behaviors including increased despair and anhedonia, which were accompanied by reduced expression of dopamine D2 receptor in the shell of nucleus accumbens (NAc) and altered serotonin signaling. While abnormal serotonin signaling is not sufficient to generate the depressive behaviors, increasing D2r expression by chronic fluoxetine (Prozac) treatment or adenoassociated virus type2 (AAV2) mediated expression of Rxrgamma or D2r in the NAc of Rxrgamma(-/-) mice normalizes depressive-like behaviors in Rxrgamma(-/-) animals. Conversely, NAc infusion of raclopride, a D2r antagonist prevents AAV2-Rxrgamma-mediated rescue of despair behaviors in Rxrgamma(-/-) mice. Combined, our data argue that control of NAc D2r expression is critical for Rxrgamma-mediated modulation of affective behaviors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / therapeutic use
  • Behavior, Animal / physiology
  • Cell Count / methods
  • Dependovirus / physiology
  • Disease Models, Animal
  • Dopamine / genetics
  • Dopamine / metabolism*
  • Dopamine Antagonists / pharmacology
  • Dose-Response Relationship, Drug
  • Fluoxetine / therapeutic use
  • Food Preferences / drug effects
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics*
  • Haloperidol / pharmacology
  • Immobility Response, Tonic / physiology
  • Mice
  • Mice, Knockout
  • Mood Disorders / drug therapy
  • Mood Disorders / genetics*
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • RNA, Messenger / metabolism
  • Receptors, Dopamine D2 / metabolism
  • Receptors, Retinoic Acid / deficiency
  • Retinoid X Receptor gamma / deficiency
  • Retinoid X Receptor gamma / physiology*
  • Serotonin / metabolism
  • Signal Transduction / genetics*


  • Antidepressive Agents
  • Dopamine Antagonists
  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Receptors, Dopamine D2
  • Receptors, Retinoic Acid
  • Retinoid X Receptor gamma
  • retinoic acid receptor beta
  • Fluoxetine
  • Serotonin
  • Haloperidol
  • Dopamine