Calcitonin gene-related peptide pre-administration acts as a novel antidepressant in stressed mice

Abstract

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...

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“…Accordingly, injection of CGRP directly into a cerebral ventricle improves learning and memory in rats, increases neurogenesis and the expression of NGF in mice subjected to combined restraint and water immersion stressors, and raises production of GDNF in a mouse model of amyotrophic lateral sclerosis …”

“…108,109 Thus, CGRP is thought to be part of the central nervous system's response to ischemia, injury, and infection, 9,[110][111][112][113] inducing repair. 106 Accordingly, injection of CGRP directly into a cerebral ventricle improves learning and memory in rats, 114 increases neurogenesis and the expression of NGF in mice subjected to combined restraint and water immersion stressors, 115 and raises production of GDNF in a mouse model of amyotrophic lateral sclerosis. 106 Indeed, CGRP has been used in two controlled human trials to reverse persistent neurological deficits, attributed to vasospastic ischemia, after aneurysm surgery.…”

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“…Moreover, CGRP seems to set in motion an array of other neuroprotective processes: It activates antiapoptotic signaling via the cyclic AMP response element‐binding transcription factor (CREB) and B cell lymphoma 2 survival protein (Bcl‐2), promotes neurotrophic signaling via insulin‐like growth factor‐1 (IGF‐1), basic fibroblast growth factor (bFGF), and nerve growth factor (NGF), reduces brain edema by inhibiting overexpression of aquaporin‐4 and, as noted, strengthens the BBB …”

“…An effect on the brain is suggested by antidepressant properties of CGRP, administered into a cerebral ventricle, in psychosocial stress . The antidepressant properties seem to be mediated by increased NGF and markedly increased angiogenesis in the hippocampus . Further, the CGRP‐mediated release of hippocampal IGF‐1 improves neurogenesis and cognition .…”