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.
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Acknowledgements
The presented study has been partially supported by Solvay Pharmaceuticals, Weesp, The Netherlands and GlaxoSmithKline, Verona, Italy. We are grateful to JI Keuker and MHP Kole for the stimulating discussions and for critically reading the manuscript. We thank Professor C Hiemke for determining fluoxetine plasma concentrations, and S Donath and A Heutz for their excellent technical assistance. Analysis of urine levels of norepinephrine and creatinine was performed at KCL Bioanalysis b.v., Leeuwarden, The Netherlands. We thank Jan Berk for his help.
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Czeh, B., Simon, M., van der Hart, M. et al. Chronic Stress Decreases the Number of Parvalbumin-Immunoreactive Interneurons in the Hippocampus: Prevention by Treatment with a Substance P Receptor (NK1) Antagonist. Neuropsychopharmacol 30, 67–79 (2005). https://doi.org/10.1038/sj.npp.1300581
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DOI: https://doi.org/10.1038/sj.npp.1300581
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