Calcitonin gene-related peptide (CGRP) is a neuropeptide that has potent vasodilator properties and is involved in various behavioral disorders. The relationship between CGRP and depression-like behavior is unclear. In this study, we used chronically stressed mice to investigate whether CGRP is involved in depression-like behavior. Each mouse was exposed to restraint and water immersion stress for 15 days. After stress exposure, mice were assessed using behavioral tests: open field test, forced swim test and sucrose preference test. Serum corticosterone levels, hippocampal proliferation and mRNA expression of neurotrophins were measured. After stress exposure, mice exhibited depression-like behavior and decreased CGRP mRNA levels in the hippocampus. Although intracerebroventricular CGRP administration (0.5 nmol) did not alter depression-like behavior after 15-day stress exposure, a single CGRP administration into the brain, before the beginning of the 15-day stress exposure, normalized the behavioral dysfunctions and increased nerve growth factor (Ngf) mRNA levels in stressed mice. Furthermore, in the mouse E14 hippocampal cell line, CGRP treatment induced increased expression of Ngf mRNA. The NGF receptor inhibitor K252a inhibited CGRP's antidepressant-like effects in stressed mice. These results suggest that CGRP expression in the mouse hippocampus is associated with depression-like behavior and changes in Ngf mRNA levels.Depression is a major psychiatric disorder that is associated with high rates of suicide, and is considered one of the most important causes of human disability. Excessive exposure to stressful life events induces the onset of behavioral disorders, including depression and post-traumatic stress disorder. The mechanisms underlying the psychopathology of depression are multifaceted, however, it is known to be accompanied by a decrease or impairment of neurogenesis in the hippocampus 1,2 . Therefore, mechanistic investigations of depression that target neurogenesis in the hippocampus are crucial. Calcitonin gene-related peptide (CGRP), a potent vasodilator 3 and neurotransmitter in the central nervous system 4 , is a 37-residue amino acid. CGRP receptors are distributed in the hypothalamus, central gray matter, ventromedial nucleus of the thalamus, amygdala, hippocampus and dentate gyrus 5 . CGRP-containing neurons are found in the hypothalamus, preoptic area, amygdala, thalamus, hippocampus (CA3 pyramidal cells), and dentate gyrus granule cells 3,6 . CGRP is reported to be involved in various behaviors suggestive of anxiety. Intracerebroventricular (i.c.v.) CGRP infusions evoke fear-like freezing 7 and anxiety behavior 8 , and improve learning and memory processing 9 . However, it is less well understood whether CGRP is involved in depression-like behavior. Clinical research shows that CGRP levels may be altered in depressed patients 10 . With this in mind, the aim of the present study was to examine whether CGRP is involved in behavioral development using a 15-day stress exposure model in mice...

Stress is known to affect neurotrophic factor expression, which induces depression-like behavior. However, whether there are time-dependent changes in neurotrophic factor mRNA expression following stress remains unclear. In the present study, we tested whether chronic stress exposure induces long-term changes in depression-related behavior, serum corticosterone, and hippocampal proliferation as well as neurotrophic factor family mRNA levels, such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and ciliary neurotrophic factor (CNTF), in the mouse hippocampus. The mRNA level of neurotrophic factors (BDNF, NGF, NT-3, and CNTF) was measured using the real-time PCR. The serum corticosterone level was evaluated by enzyme-linked immunosorbent assay, and, for each subject, the hippocampal proliferation was examined by 5-bromo-2-deoxyuridine immunostaining. Mice exhibited depression-like behavior in the forced-swim test (FST) and decreased BDNF mRNA and hippocampal proliferation in the middle of the stress exposure. After 15 days of stress exposure, we observed increased immobility in the FST, serum corticosterone levels, and BDNF mRNA levels and degenerated hippocampal proliferation, maintained for at least 2 weeks. Anhedonia-like behavior in the sucrose preference test and NGF mRNA levels were decreased following 15 days of stress. NGF mRNA levels were significantly higher 1 week after stress exposure. The current data demonstrate that chronic stress exposure induces prolonged BDNF and NGF mRNA changes and increases corticosterone levels and depression-like behavior in the FST, but does not alter other neurotrophic factors or performance in the sucrose preference test.

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Numerous rodent models of depression have been reported, most requiring a long experimental period and signiˆcant eŠort. We explored a new potential mouse model for depression by investigating whether exposure to a 15-day chronic stress paradigm could induce depression-like behavior in ICR mice. Animals in the stress-exposed groups were subjected to 3 h of restraint while immersed in a 28°C water bath daily for 15 consecutive days. Immobility time in the forced swim test was increased in the chronic stress-exposed mice compared with the controls. Serum corticosterone levels were also much higher in the stressed mice than in the control mice. Hippocampal cell survival (BrdU-positive cells) and neurotrophic factor (NGF, TrkA) mRNA levels were signiˆcantly decreased in the chronic stress-exposed mice compared with controls. Administration of the anti-depressant drugs clomipramine (20 mg/kg/d) or imipramine (30 mg/kg/d) did not change the immobility time in the forced swim test, but treatment with lithium (100 mg/kg/d) did result in slight improvement. These results suggest that this 15-day chronic stress paradigm can induce depression-like behavior and neurological changes, in a short time and with minimal eŠort, facilitating the assessment of treatments for depression.