Orexin and fear; potential role of OX1R antagonist for treating anxiety disorders and PTSD

  • Soya Shingo
    筑波大学国際統合睡眠医科学研究機構

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  • オレキシンと恐怖;不安障害やPTSDの治療薬としてのOX1R拮抗薬の可能性

Abstract

<p>Fear is an important physiological function for survival. It appears when animals or humans are confronted with an environmental threat. The amygdala has been shown to play a highly important role in emergence of a fear-related behavior such as freezing that only occurs when the environment contains some elements suggestive of danger. Previous studies showed that hypothalamic orexin neurons are activated by fearful stimuli to evoke a 'defense reaction' with an increase in arousal level and sympathetic outflow to deal with the imminent danger. However, how this system contributes to the emergence of fear-related behavior is still unclear. We took cued and contextual fear conditioning experiment using orexin 1 receptor knockout (OX1R-/-) and orexin 2 receptor knockout (OX2R-/-) and orexin double receptor knockout (OX1R-/-; OX2R -/-) and prepro-orexin knockout (preproOX-/-) mice. We found that OX1R-/- and OX1R-/-; OX2R -/- and preproOX-/- showed abnormality in both cued and contextual fear conditioning test suggesting the orexin system might be important for fear memory formation and/or consolidation and/or retrieval mainly via OX1R signaling. Orexin neurons in the hypothalamus send excitatory innervations to noradrenergic neurons in the locus coeruleus (NALC) which abundantly express OX1R and send projections to the lateral amygdala (LA), which is known as the critical region for fear memory formation. Opto/chemogenetic inhibition of this di-synaptic orexin → NALC → LA pathway or pharmacological blockade of OX1R reduces cue-induced fear expression. Inversely, excitatory manipulation of this pathway after fear conditioning induces fear-related behavior. Although, fear memory helps animals respond precisely to a context or cue previously paired with an aversive stimulus, fear-related behavior is sometimes evoked even in a distinct context containing some similar elements, which is known as fear generalization. Our data suggests that the orexin → NALC → LA pathway might explain a part of the mechanism of fear generalization. We also discuss about the potential effectiveness of OX1R antagonists for treating excessive fear response or overgeneralization seen in anxiety disorder and post-traumatic stress disorder (PTSD).</p>

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