A Shift in the Activation of Serotonergic and Non-serotonergic Neurons in the Dorsal Raphe Lateral Wings Subnucleus Underlies the Panicolytic-Like Effect of Fluoxetine in Rats

Mol Neurobiol. 2019 Sep;56(9):6487-6500. doi: 10.1007/s12035-019-1536-z. Epub 2019 Mar 7.


A wealth of evidence indicates that the lateral wings subnucleus of the dorsal raphe nucleus (lwDR) is implicated in the processing of panic-associated stimuli. Escape expression in the elevated T-maze, considered a panic-related defensive behavior, markedly and selectively recruits non-serotonergic cells within this DR subregion and in the dorsal periaqueductal gray (dPAG), another key panic-associated area. However, whether anti-panic drugs may interfere with this pattern of neuronal activation is still unknown. In the present study, the effects of acute (10 mg/kg) or chronic fluoxetine (10 mg/kg/daily/21 days) treatment on the number of serotonergic and non-serotonergic cells induced by escape expression within the rat DR and PAG subnuclei were investigated by immunochemistry. The results showed that chronic, but not acute, treatment with fluoxetine impaired escape expression, indicating a panicolytic-like effect, and markedly decreased the number of non-serotonergic cells that were recruited in the lwDR and dPAG. The same treatment selectively increased the number of serotonergic neurons within the lwDR. Our immunochemistry analyses also revealed that the non-serotonergic cells recruited in the lwDR and dPAG by the escape expression were not nitrergic. Overall, our findings suggest that the anti-panic effect of chronic treatment with fluoxetine is mediated by stimulation of the lwDR-dPAG pathway that controls the expression of panic-associated escape behaviors.

Keywords: Antidepressant; Dorsal raphe; Elevated T-maze; Nitric oxide; Panic; Serotonin.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Dorsal Raphe Nucleus / drug effects
  • Dorsal Raphe Nucleus / metabolism*
  • Fluoxetine / adverse effects*
  • Male
  • Nitric Oxide Synthase Type I / metabolism
  • Panic / drug effects*
  • Periaqueductal Gray / drug effects
  • Periaqueductal Gray / metabolism
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats, Wistar
  • Serotonergic Neurons / drug effects
  • Serotonergic Neurons / metabolism*


  • Proto-Oncogene Proteins c-fos
  • Fluoxetine
  • Nitric Oxide Synthase Type I