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It has been suggested by studies in animals and humans that substance P (SP) and its receptor neurokinin 1 (NK1R) play an important role in the pathology of depression. The pharmacological blockade or genetic deletion of the NK1 receptor, or the substance P coding gene
tac1 led to a decreased emotionality and a reduction of depression-related behaviours in different animal models. In order to characterize molecular changes associated with reduced SP-NK1 signalling in animal models of depression, we assessed the regulation of the CRH system. First,
tac1
−/− animals and
tac1
+/+ controls were subjected to bulbectomy, which induces physiological and behavioural changes that are relevant to depression. We demonstrate that
tac1
−/− animals, in contrast to
tac1
+/+ controls, do not show anhedonia in the saccharine preference test after bulbectomy. Next, we studied expression levels of CRH, the receptors CRHR1 and CRHR2, and the binding protein CRHBP in the cortex and paraventricular nucleus using real-time RT-PCR. Our results show a strong induction of CRH, CRHBP and CRHR1 expression in the cortex of
tac1
−/−, but not in
tac1
+/+ animals. In the PVN, bulbectomized
tac1
−/− mice showed an elevated expression of CRHR1 and CRHR2. These results show that substance P/NKA is involved in modulating CRH signalling in an animal model of depression.