Effects of intranasal administration of CGRP on contextual fear memory

Abstract

Calcitonin gene-related peptide (CGRP) suppresses fear memory retention by intracerebroventricular administration in mice. We propose that CGRP holds potential as a therapeutic drug candidate for posttraumatic stress disorder. However, brain injection is not suitable for clinical application. Intranasal administration could transfer a small molecular drug to the brain without blockage from the blood-brain barrier, delivering rapid effects. In this study, we investigated the effect of intranasal administration of CGRP on fear memory. Eight-week-old C57BL6J male mice were administered with saline or CGRP intranasally. The concentration of CGRP in the cerebrospinal fluid and hippocampus 30 minutes after nasal administration of CGRP was significantly higher than saline. Moreover, CGRP suppressed memory retention without effects to the process of reconsolidation and extinction. We found that intranasal CGRP significantly increased the expression of protein kinase D (PKD), phosphorylated histone deacetylase 5 (p-HDAC5), and neuronal PAS domain protein 4 (Npas4) in the hippocampus. CGRP-mediated impairment of fear memory and increases of Npas4 expression were attenuated significantly by the CGRP receptor antagonist, BIBN4096. Our data demonstrate that intranasal CGRP successfully entered the brain and suppressed the retention of fear memory via activating the PKD/p-HDAC5/Npas4 pathway.