Retinoid X Receptor Gamma Control of Affective Behaviors Involves Dopaminergic Signaling in Mice

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 Rxr gamma 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 Rxr gamma or D2r in the NAc of Rxr gamma(-/-) mice normalizes depressive-like behaviors in Rxr gamma(-/-) animals. Conversely, NAc infusion of raclopride, a D2r antagonist prevents AAV2-Rxr gamma-mediated rescue of despair behaviors in Rxr gamma(-/-) mice. Combined, our data argue that control of NAc D2r expression is critical for Rxr gamma-mediated modulation of affective behaviors.