Abstract

Orexins peptides exert a prominent role in arousal-related processes including stress responding, by activating orexin-1 (OX1R) and orexin-2 (OX2R) receptors located widely throughout the brain. Stress or orexin administration stimulates hyperarousal, adrenocorticotropic hormone (ACTH) and corticosterone release, and selective OX1R blockade can attenuate several stress-induced behavioral and cardiovascular responses but not the hypothalamic-pituitary-adrenal (HPA) axis activation. As opposed to OX1R, OX2R are preferentially expressed in the paraventricular hypothalamic nucleus which is involved in the HPA axis regulation. In the present study, we investigated the effects of a psychological stress elicited by cage exchange (CE) on ACTH release in two murine models (genetic and pharmacological) of selective OX2R inhibition. CE-induced stress produced a significant increase in ACTH serum levels. Mice lacking the OX2R exhibited a blunted stress response. Stress-induced ACTH release was absent in mice pre-treated with the selective OX2R antagonist JNJ-42847922 (30 mg/kg po), whereas pre-treatment with the dual OX1/2R antagonist SB-649868 (30 mg/kg po) only partially attenuated the increase of ACTH. To assess whether the intrinsic and distinct sleep-promoting properties of each antagonist could account for the differential stress response, a separate group of mice implanted with electrodes for standard sleep recording were orally dosed with JNJ-42847922 or SB-649868 during the light phase. While both compounds reduced the latency to non-rapid eye movement (NREM) sleep without affecting its duration, a prevalent REM-sleep promoting effect was observed only in mice treated with the dual OX1/2R antagonist. These data indicate that in a psychological stress model, genetic or pharmacological inhibition of OX2R markedly attenuated stress-induced ACTH secretion, as a separately mediated effect from the NREM sleep induction of OX2R antagonism.

Highlights

  • Orexin-A and -B are excitatory neuropeptides produced by lateral hypothalamic neurons that play important roles in the regulation of sleep/wake cycles, energy metabolism, reward-directed behavior, anxious arousal, stress responses and monoaminergic neurotransmitter release via a relatively discrete network of neuroanatomical projections (Li et al, 2014; Sakurai, 2014)

  • cage exchange (CE)-induced stress produced a significant increase in adrenocorticotropic hormone (ACTH) serum levels in WT whereas mice lacking the OX2R exhibited a blunted stress response relative to their respective control conditions under which ACTH levels were very similar to each other (Figure 1B)

  • Stress-induced ACTH release was virtually absent in mice pre-treated with the selective OX2R antagonist JNJ-42847922

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Summary

Introduction

Orexin-A and -B are excitatory neuropeptides produced by lateral hypothalamic neurons that play important roles in the regulation of sleep/wake cycles, energy metabolism, reward-directed behavior, anxious arousal, stress responses and monoaminergic neurotransmitter release via a relatively discrete network of neuroanatomical projections (Li et al, 2014; Sakurai, 2014). The best-characterized orexinergic system involves the OX2R located on histaminergic neurons in the tuberomammillary nuclei of the hypothalamus, where these receptors play a critical role in wake promotion (Eriksson et al, 2001). Stress or orexin administration stimulates hyperarousal, adrenocorticotropic hormone (ACTH) and corticosterone release (Berridge et al, 2010) and selective OX1R blockade can attenuate several stress-induced behavioral and cardiovascular responses but not the HPA axis activation (Bonaventure et al, 2015b). As opposed to OX1R, OX2R are predominantly expressed in the paraventricular hypothalamic nucleus which is involved in the HPA axis regulation (Trivedi et al, 1998; Marcus et al, 2001)

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