Mesolimbic dopamine system and its modulation by vitamin D in a chronic mild stress model of depression in the rat

Behav Brain Res. 2019 Jan 1:356:156-169. doi: 10.1016/j.bbr.2018.08.020. Epub 2018 Aug 23.


Depression, a common mood disorder, involves anhedonia and defects in reward circuits and mesolimbic dopamine transmission in the striatum and nucleus accumbens (NAc). Active vitamin-D, (1,25-(OH)2 vitamin-D3), exerts protective and regulatory effects on the brain dopamine system. In this study, key depression-like symptoms were induced in rats by chronic mild-stress (CMS) and the comparative effect of treatment with 1,25-(OH)2 vitamin-D3 (5, 10 μg/kg, or vehicle; i.p., twice weekly) or fluoxetine (5 mg/kg or vehicle, i.p., daily) on anhedonic behavior, locomotor activity and anxiety-like behavior was examined using sucrose preference test (SPT), open field test (OFT) and novel object exploration test (NOT), respectively. We also measured serum corticosterone levels and dopamine transporter-immunoreactivity (DAT-ir) levels in NAc shell and core. CMS exposure for 3 weeks was followed by a SPT and thereafter CMS was continued for 5 weeks, along with vitamin-D or fluoxetine treatment and further testing, which was concluded with another SPT. Vitamin-D treatment enhanced sucrose preference (P < 0.01; an hedonic effect) and increased object exploration (P < 0.01) in CMS rats. CMS significantly reduced the level of DAT-ir in NAc (P < 0.0001). Vitamin-D treatment restored/increased DAT-ir levels (P < 0.0001) in CMS rat NAc (core/ shell), compared to levels in fluoxetine treated and non-treated CMS rats. Vitamin-D did not alter locomotor activity or produce an anxiolytic effect in the OFT. These data suggest that similar to the antidepressant, fluoxetine, regular vitamin-D treatment can improve 'anhedonia-like symptoms' in rats subjected to CMS, probably by regulating the effect of dopamine-related actions in the NAc.

Keywords: Chronic mild stress; Depression; Fluoxetine; Nucleus accumbens; Rat; Vitamin-D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anhedonia / drug effects*
  • Anhedonia / physiology
  • Animals
  • Antidepressive Agents / pharmacology
  • Anxiety / metabolism
  • Anxiety Disorders / drug therapy
  • Behavior, Animal / physiology
  • Brain / metabolism
  • Depression / metabolism*
  • Depressive Disorder / drug therapy
  • Disease Models, Animal
  • Dopamine / metabolism
  • Dopamine / pharmacology
  • Dopamine Plasma Membrane Transport Proteins / drug effects
  • Male
  • Nucleus Accumbens / metabolism
  • Rats
  • Rats, Wistar
  • Stress, Psychological
  • Vitamin D / metabolism
  • Vitamin D / physiology*
  • Vitamins / pharmacology


  • Antidepressive Agents
  • Dopamine Plasma Membrane Transport Proteins
  • Vitamins
  • Vitamin D
  • Dopamine