Olfactory bulbectomized (OBX) mice exhibit depressive-like behaviors as assessed by the tail suspension test (TST) and the forced swim test (FST). Interestingly, chronic intraperitoneal administration (1 mg/kg/day) of nefiracetam (DM-9384), a prototype cognitive enhancer, significantly improved depressive-like behaviors as well as spatial reference memory assessed by Y-maze task. As previously reported (Moriguchi, S., Han, F., Nakagawasai, O., Tadano, T., Fukunaga, K., 2006. Decreased calcium/calmoculin-dependent protein kinase II and protein kinase C activities mediate impairment of hippocampal long-term potentiation in the olfactory bulbectomized mice. J. Neurochem. 97, 22-29), decreased activities of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-regulated kinase (ERK) in the hippocampal CA1 region and amygdala were observed in OBX mice. Nefiracetam treatment (1 mg/kg/day) significantly elevated CaMKII but not ERK activities in the amygdala, prefrontal cortex and hippocampal CA1 regions. In addition, we found an elevation of cAMP response element-binding protein (CREB) phosphorylation in the amygdala and prefrontal cortex but not in the hippocampal CA1 region. Increased CREB phosphorylation was associated with activation of CaMKI and CaMKIV as well as CaMKII in these regions. Taken together, in addition to CaMKII, CaMKI and CaMKIV activation mediated by nefiracetam treatment might mediate CREB phosphorylation following chronic nefiracetam treatment, thereby eliciting an anti-depressive and cognition-enhancing effect on OBX mice.