Brain Metabolic Profile after Intranasal vs. Intraperitoneal Clomipramine Treatment in Rats with Ultrasound Model of Depression.

Olga Abramova,Anna Morozova,Eugene Zubkov,Olga Gurina,Kristina Soloveva,Artemiy Silantyev,Alexander Majouga,Vladimir Chekhonin,Yana Zorkina,Valeria Ushakova,Timur Syunyakov

doi:10.3390/ijms22179598

Abstract

Background: Molecular mechanisms of depression remain unclear. The brain metabolome after antidepressant therapy is poorly understood and had not been performed for different routes of drug administration before the present study. Rats were exposed to chronic ultrasound stress and treated with intranasal and intraperitoneal clomipramine. We then analyzed 28 metabolites in the frontal cortex and hippocampus. Methods: Rats’ behavior was identified in such tests: social interaction, sucrose preference, forced swim, and Morris water maze. Metabolic analysis was performed with liquid chromatography. Results: After ultrasound stress pronounced depressive-like behavior, clomipramine had an equally antidepressant effect after intranasal and intraperitoneal administration on behavior. Ultrasound stress contributed to changes of the metabolomic pathways associated with pathophysiology of depression. Clomipramine affected global metabolome in frontal cortex and hippocampus in a different way that depended on the route of administration. Intranasal route was associated with more significant changes of metabolites composition in the frontal cortex compared to the control and ultrasound groups while the intraperitoneal route corresponded with more profound changes in hippocampal metabolome compared to other groups. Since far metabolic processes in the brain can change in many ways depending on different routes of administration, the antidepressant therapy should also be evaluated from this point of view.

Highlights

IntroductionThe brain metabolome after antidepressant therapy is poorly understood and had not been performed for different routes of drug administration before the present study
The stress induced by exposure to variable frequency ultrasound (US) in a threeweek period caused depressive-like behavior in rats
Clomipramine administration has antidepressant effects, and there was no difference observed in the efficacy of intranasal and intraperitoneal administration

Summary

Introduction

The brain metabolome after antidepressant therapy is poorly understood and had not been performed for different routes of drug administration before the present study. Results: After ultrasound stress pronounced depressive-like behavior, clomipramine had an antidepressant effect after intranasal and intraperitoneal administration on behavior. Clomipramine affected global metabolome in frontal cortex and hippocampus in a different way that depended on the route of administration. Intranasal route was associated with more significant changes of metabolites composition in the frontal cortex compared to the control and ultrasound groups while the intraperitoneal route corresponded with more profound changes in hippocampal metabolome compared to other groups. Since far metabolic processes in the brain can change in many ways depending on different routes of administration, the antidepressant therapy should be evaluated from this point of view

Methods

Results

Discussion

Conclusion