32. OREXIN 1 RECEPTOR ANTAGONISM EXACERBATES SLEEP DEFICITS AND REDUCES ANXIETY IN A TAU TRANSGENIC MOUSE MODEL OF ALZHEIMER'S DISEASE

Abstract

Introduction

Alzheimer's disease (AD) affects more than 55 million people globally and current pharmacological treatments for symptoms remain limited. Neurons producing orexin peptides located in the lateral hypothalamus project widely throughout the brain, and represent a novel target in AD. Orexins bind to orexin 1 and orexin 2 receptors (OX1Rs and OX2Rs). Dual orexin receptor antagonists (DORAs) are an effective treatment for insomnia in AD as they improve REM sleep and memory consolidation. They also reduce phosphor-tau variants and amyloid-beta in human CSF. OX1Rs are involved in stress responses and motivated behaviours. OX1R antagonists remain underexplored and offer a novel potential treatment modality for psychiatric disorders and, unlike DORAs, are not hypnotic.

Methods

We pharmacologically antagonised OX1Rs in an AD mouse model with the aim of reducing psychiatric-like behaviours without somnolence. Male and female PS19 mice (an AD mouse model with overexpression of P301S mutant human tau), and wild type littermates, were dosed daily p.o. with the OX1R antagonist 1-SORA-51 (60mg/kg/d) or vehicle. Vigilance states were recorded using polysomnography recordings and anxiety-like behaviours were assessed using a range of behavioural tests.

Results

Male and female transgenic mice showed significant REM sleep deficits, with males also exhibiting decreased non-REM sleep and increased wakefulness. Male transgenic mice demonstrated hyperlocomotion in the open field test. Unexpectedly, the OX1R antagonist 1-SORA-51 exacerbated REM sleep deficits in male tau transgenic mice and, contrastingly, rescued anxiety-like behaviours in the open field assay.

Conclusions

OX1R antagonism in AD may be effective in ameliorating anxiety symptoms during the daytime, while discordantly worsening REM sleep deficits at night.