Intracerebroventricular Administration of Interferon-Alpha Induced Depressive-Like Behaviors and Neurotransmitter Changes in Rhesus Monkeys.

Zhifei Li,Lei Xiong,Xiaoman Lv,Dongdong Qin,Zhaofu Li,Zhaoxia Li,Xintian Hu

doi:10.3389/fnins.2020.585604

Abstract

Interferon-alpha (IFN-α) is a cytokine widely used in the treatment of brain cancers and virus infections with side effects including causing depression. Monoamine neurotransmitter systems have been found playing important roles in peripheral IFN-α-induced depression, but how peripheral IFN-α accesses the central nervous system and contributes to the development of depression is poorly known. This study aimed to develop a non-human primate model using long-term intracerebroventricular (i.c.v.) administration of IFN-α (5 days/week for 6 weeks), to observe the induced depressive-like behaviors and to explore the contributions of monoamine neurotransmitter systems in the development of depression. In monkeys receiving i.c.v. IFN-α administration, anhedonia was observed as decreases of sucrose consumption, along with depressive-like symptoms including increased huddling behavior, decreases of spontaneous and reactive locomotion in home cage, as well as reduced exploration and increased motionless in the open field. Chronic central IFN-α infusion significantly increased the cerebrospinal fluid (CSF) concentrations of noradrenaline (NA), and 3,4-dihydroxyphenylacetic acid (DOPAC), but not 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA). These CSF monoamine metabolites showed associations with some specific depression-related behaviors. In conclusion, central IFN-α administration induced anhedonia and depression-related behaviors comparable to the results with peripheral administration, and the development of depression was associated with the dysfunction of monoamine neurotransmitters.

Highlights

Interferon-alpha (IFN-α) is a pleiotropic cytokine released in response to viral infection, which enhances the cellular immune response
Thereafter, we compared the volume of sucrose intake, which was significantly decreased in Adm2 compared with the Pre phase in the IFN group (Figure 1C, ∗p = 0.049)
Peripheral IFN-α-induced depression is more associated with somatic symptoms and less associated with symptoms of mood and negative cognition, compared with patients with major depressive disorder (Capuron et al, 2009; Su et al, 2019)

Summary

Introduction

Interferon-alpha (IFN-α) is a pleiotropic cytokine released in response to viral infection, which enhances the cellular immune response. Intraventricular administration of IFN-α was used to treat central nervous system (CNS) diseases induced by viral infection such as subacute sclerosing panencephalitis (SSPE) (Yalaz et al, 1992; Kwak et al, 2019). Recruitment of cytokines including the IFN-α during CNS inflammation contributes to the development of depression (Bodnar et al, 2018; Su et al, 2019). How peripherally administrated IFN-α (e.g., intravenous and intramuscular injection) induces depression has been well studied in animal models including rodents (Hoyo-Becerra et al, 2015) and non-human primates (Felger et al, 2007). Monkeys that showed IFNα-induced huddling behavior had lower cerebrospinal fluid (CSF) concentrations of homovanillic acid (HVA), a dopamine metabolite (Felger et al, 2007)

Objectives

Methods

Results

Conclusion