Omega-3 Fatty Acid Deficient Male Rats Exhibit Abnormal Behavioral Activation in the Forced Swim Test Following Chronic Fluoxetine Treatment: Association With Altered 5-HT1A and alpha2A Adrenergic Receptor Expression

J Psychiatr Res. 2014 Mar;50:42-50. doi: 10.1016/j.jpsychires.2013.11.008. Epub 2013 Dec 6.


Omega-3 fatty acid deficiency during development leads to enduing alterations in central monoamine neurotransmission in rat brain. Here we investigated the effects of omega-3 fatty acid deficiency on behavioral and neurochemical responses to chronic fluoxetine (FLX) treatment. Male rats were fed diets with (CON, n = 34) or without (DEF, n = 30) the omega-3 fatty acid precursor alpha-linolenic acid (ALA) during peri-adolescent development (P21-P90). A subset of CON (n = 14) and DEF (n = 12) rats were administered FLX (10 mg/kg/d) through their drinking water for 30 d beginning on P60. The forced swimming test (FST) was initiated on P90, and regional brain mRNA markers of serotonin and noradrenaline neurotransmission were determined. Dietary ALA depletion led to significant reductions in frontal cortex docosahexaenoic acid (DHA, 22:6n-3) composition in DEF (-26%, p = 0.0001) and DEF + FLX (-32%, p = 0.0001) rats. Plasma FLX and norfluoxetine concentrations did not different between FLX-treated DEF and CON rats. During the 15-min FST pretest, DEF + FLX rats exhibited significantly greater climbing behavior compared with CON + FLX rats. During the 5-min test trial, FLX treatment reduced immobility and increased swimming in CON and DEF rats, and only DEF + FLX rats exhibited significant elevations in climbing behavior. DEF + FLX rats exhibited greater midbrain, and lower frontal cortex, 5-HT1A mRNA expression compared with all groups including CON + FLX rats. DEF + FLX rats also exhibited greater midbrain alpha2A adrenergic receptor mRNA expression which was positively correlated with climbing behavior in the FST. These preclinical data demonstrate that low omega-3 fatty acid status leads to abnormal behavioral and neurochemical responses to chronic FLX treatment in male rats.

Keywords: 5-HT(1A) autoreceptor; Alpha(2A) adrenergic receptor; Docosahexaenoic acid; Fluoxetine; Forced swim test; Omega-3 fatty acid; Serotonin transporter; Tryptophan hydroxylase-2.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Body Weight / drug effects
  • Brain / drug effects*
  • Brain / growth & development
  • Brain / metabolism
  • Diet
  • Fatty Acids, Omega-3 / metabolism*
  • Fluoxetine / analogs & derivatives
  • Fluoxetine / blood
  • Fluoxetine / pharmacology*
  • Male
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • RNA, Messenger / metabolism
  • Random Allocation
  • Rats
  • Rats, Long-Evans
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Receptors, Adrenergic, alpha-2 / metabolism
  • Serotonin Uptake Inhibitors / blood
  • Serotonin Uptake Inhibitors / pharmacology*
  • Stress, Psychological / drug therapy*
  • Stress, Psychological / metabolism*
  • Swimming
  • alpha-Linolenic Acid / deficiency


  • Adra2a protein, rat
  • Fatty Acids, Omega-3
  • RNA, Messenger
  • Receptors, Adrenergic, alpha-2
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • alpha-Linolenic Acid
  • Receptor, Serotonin, 5-HT1A
  • norfluoxetine