Chronic Stress Decreases the Number of Parvalbumin-Immunoreactive Interneurons in the Hippocampus: Prevention by Treatment With a Substance P Receptor (NK1) Antagonist

Neuropsychopharmacology. 2005 Jan;30(1):67-79. doi: 10.1038/sj.npp.1300581.

Abstract

Previous studies have demonstrated that stress may affect the hippocampal GABAergic system. Here, we examined whether long-term psychosocial stress influenced the number of parvalbumin-containing GABAergic cells, known to provide the most powerful inhibitory input to the perisomatic region of principal cells. Adult male tree shrews were submitted to 5 weeks of stress, after which immunocytochemical and quantitative stereological techniques were used to estimate the total number of hippocampal parvalbumin-immunoreactive (PV-IR) neurons. Stress significantly decreased the number of PV-IR cells in the dentate gyrus (DG) (-33%), CA2 (-28%), and CA3 (-29%), whereas the CA1 was not affected. Additionally, we examined whether antidepressant treatment offered protection from this stress-induced effect. We administered fluoxetine (15 mg/kg per day) and SLV-323 (20 mg/kg per day), a novel neurokinin 1 receptor (NK1R) antagonist, because the NK1R has been proposed as a possible target for novel antidepressant therapies. Animals were subjected to a 7-day period of psychosocial stress before the onset of daily oral administration of the drugs, with stress continued throughout the 28-day treatment period. NK1R antagonist administration completely prevented the stress-induced reduction of the number of PV-IR interneurons, whereas fluoxetine attenuated this decrement in the DG, without affecting the CA2 and CA3. The effect of stress on interneuron numbers may reflect real cell loss; alternatively, parvalbumin concentration is diminished in the neurons, which might indicate a compensatory attempt. In either case, antidepressant treatment offered protection from the effect of stress and appears to modulate the hippocampal GABAergic system. Furthermore, the NK1R antagonist SLV-323 showed neurobiological efficacy similar to that of fluoxetine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Count
  • Chronic Disease
  • Conflict, Psychological
  • Creatinine / urine
  • Fluoxetine / pharmacology
  • Hippocampus / cytology*
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Immunohistochemistry
  • Interneurons / metabolism*
  • Male
  • Neurokinin-1 Receptor Antagonists*
  • Norepinephrine / urine
  • Organ Size / drug effects
  • Organ Size / physiology
  • Parvalbumins / metabolism*
  • Serotonin Uptake Inhibitors / pharmacology
  • Stress, Psychological / pathology*
  • Testis / drug effects
  • Tupaia / physiology*

Substances

  • Neurokinin-1 Receptor Antagonists
  • Parvalbumins
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Creatinine
  • Norepinephrine