Chronic stress decreases the number of parvalbumin-immunoreactive interneurons in the hippocampus: prevention by treatment with a substance P receptor (NK1) antagonist.
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.
Czeh
Boldizsár
B
Clinical Neurobiology Laboratory, German Primate Center, Göttingen, Germany. bczeh@dpz.gwdg.de
Simon
Mária
M
van der Hart
Marieke Gc
MG
Schmelting
Barthel
B
Hesselink
Mayke B
MB
Fuchs
Eberhard
E
D000818:Animals; D002452:Cell Count; D002908:Chronic Disease; D003220:Conflict, Psychological; D003404:Creatinine / Q000652:urine; D005473:Fluoxetine / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D007395:Interneurons / Q000378:metabolism*; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D009638:Norepinephrine / Q000652:urine; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D010320:Parvalbumins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013315:Stress, Psychological / Q000473:pathology*; D013737:Testis / Q000187:drug effects; D014417:Tupaia / Q000502:physiology*
D003404:Creatinine; D005473:Fluoxetine; D064729:Neurokinin-1 Receptor Antagonists; D009638:Norepinephrine; D010320:Parvalbumins; D017367:Selective Serotonin Reuptake Inhibitors