Background: The calcitonin gene-related peptide (CGRP) is a neuropeptide that is released from capsaicin-sensitive nerves as a potent vasodilator involved in nociceptive transmission. While CGRP has been rigorously studied for its role in migraines owing to its vasodilation and inflammation activities, the effects of CGRP overexpression on depressive-like behaviors remain insufficiently understood. Methods: In the present study, we performed a battery of behavioral tests, including the social interaction test, open field test, and sucrose preference test, to evaluate social defeat stress using male C57BL6J or CGRP overexpression in transgenic (Tg) mice (CGRP Tg). We performed mRNA and protein analyses on the brain-derived neurotrophic factor (BDNF), phosphorylated Akt, mTOR, and p70S6K in the hippocampi. Results: CGRP Tg mice showed increased levels of Bdnf mRNAs, low locomotor activity, and no deficits in social interaction, which indicate that CGRP Tg mice exhibit stress resistance and not depression. However, the open field test significantly decreased after 15-day social defeat stress exposure. We also evaluated depressive-like behavior using the sucrose preference and social interaction tests. Our data indicate that defeated CGRP Tg mice exhibited a depressive-like phenotype, which was inferred from increased social avoidance and reduced sucrose preference compared with non-defeated controls. Although stress exposure did not change the BDNF levels in CGRP Tg mice, it significantly decreased the expression levels of p-Akt, p-mTOR and p-p70S6K in the mice hippocampi. We conclude that CGRP-overexpressing Tg mice have normal sensitivity to stress and down-regulated hippocampal Akt/mTOR/p70S6K pathways.
