Glucocorticoid Receptor Antagonist Mifepristone Does Not Alter Innate Anxiety-Like Behavior in Genetically-Selected Marchigian Sardinian (msP) Rats.

Valentina Vozella,Nazzareno Cannella,Bryan Cruz,Luis A Natividad,Eric P Zorrilla,Scott Edwards,Marisa Roberto,Federica Benvenuti,Roberto Ciccocioppo

doi:10.3390/ijms22063095

Abstract

Marchigian Sardinian alcohol-preferring (msP) rats serve as a unique model of heightened alcohol preference and anxiety disorders. Their innate enhanced stress and poor stress-coping strategies are driven by a genetic polymorphism of the corticotropin-releasing factor receptor 1 (CRF1) in brain areas involved in glucocorticoid signaling. The activation of glucocorticoid receptors (GRs) regulates the stress response, making GRs a candidate target to treat stress and anxiety. Here, we examined whether mifepristone, a GR antagonist known to reduce alcohol drinking in dependent rats, decreases innate symptoms of anxiety in msPs. Male and female msPs were compared to non-selected Wistar counterparts across three separate behavioral tests. We assessed anxiety-like behavior via the novelty-induced hypophagia (NIH) assay. Since sleep disturbances and hyperarousal are common features of stress-related disorders, we measured sleeping patterns using the comprehensive lab monitoring system (CLAMS) and stress sensitivity using acoustic startle measures. Rats received an acute administration of vehicle or mifepristone (60 mg/kg) 90 min prior to testing on NIH, acoustic startle response, and CLAMS. Our results revealed that both male and female msPs display greater anxiety-like behaviors as well as enhanced acoustic startle responses compared to Wistar counterparts. Male msPs also displayed reduced sleeping bout duration versus Wistars, and female msPs displayed greater acoustic startle responses versus male msPs. Importantly, the enhanced anxiety-like behavior and startle responses were not reduced by mifepristone. Together, these findings suggest that increased expression of stress-related behaviors in msPs are not solely mediated by acute activation of GRs.

Highlights

To determine whether acute mifepristone administration reduces anxiety-like behavior in a genotype-specific manner, male and female Wistar and Marchigian Sardinian alcohol-preferring (msP) rats were pre-exposed to palatable chocolate pellets and tested under novel environmental conditions using the novelty-induced hypophagia procedure
We found that male msPs in general displayed a greater latency to eat under novelty stress conditions as compared to male Wistar rats, main effect of genotype F(1,40) = 42.52, p = 0.001 (Figure 1A)
A single systemic mifepristone administration did not affect the latency to eat or the intake of chocolate pellets in male msPs, suggesting that the enhanced anxiety-like phenotype in msPs is not ameliorated by an acute administration of glucocorticoid receptors (GRs) antagonist mifepristone

Summary

Introduction

Exposure to stressors initiates the activation of the HPA axis, which results in an increased release of corticotropin-releasing factor (CRF) from specific subnuclei of the hypothalamus, such as the paraventricular nucleus (PVN) [2]. 1 (CRF1) through CRF stimulates the release of adrenocorticotropic hormone from the anterior pituitary and subsequent glucocorticoid secretion from the adrenal glands. This systemic stress response is terminated through a negative feedback process on the HPA axis when glucocorticoids bind to glucocorticoid receptors (GRs) [3], which are enriched in the hypothalamic PVN [4]. GR is considered to play an essential role in modulating both adaptive and maladaptive stress-associated behaviors [10]

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