AbstractNeurokinin 1 (NK‐1) receptor knockout mice showed behavioral responses similar to animals chronically treated with antidepressants. The aim of this study was to analyse, in NK‐1 receptor knockout, the molecular modifications of signaling pathways involved in the pathophysiology of depression and antidepressant mechanism. We found, in total cell cytosol from the prefrontal/frontal cortex, hippocampus and striatum, a marked up‐regulation of Ca2+‐independent enzymatic activity and Thr286 autophosphorylation of Ca2+/calmodulin‐dependent protein kinase (CaMK) II. Similar changes in CaMKII regulation were previously observed in rats chronically treated with antidepressants. In striatum, up‐regulation of the activity and phosphorylation of CaMKII was also found in the homogenate and synaptosomes. No major changes were observed in the Ca2+‐dependent kinase activity, with the exception of homogenate from the prefrontal/frontal cortex. We also analysed the expression and phosphorylation of presynaptic proteins, which modulate synaptic vesicle trafficking and exocytosis, and found a marked decrease in synapsin I total expression and basal phosphorylation of Ser603 (the phosphorylation site for CaMKII) in the prefrontal/frontal cortex. Accordingly, the Ca2+/calmodulin‐dependent posthoc endogenous phosphorylation of synapsin I in the same area was increased. The knockout of NK‐1 receptor had no consequences on the expression or phosphorylation levels of the transcription factor cAMP‐responsive element‐binding protein and its regulating kinase CaMKIV. However, phosphorylation of ERK1/2‐mitogen‐activated protein kinases was reduced in the hippocampus and striatum, again resembling an effect previously observed in antidepressant‐treated rats. These results show similarities between NK‐1 knockouts and animals chronically treated with antidepressants and support the putative antidepressant activity of NK‐1 receptor antagonists.