Selective orexin receptor cross-over treatment increases resilience and expression of neuroplastic signaling genes

Social stress, beneficial for evaluating threats and resource opportunities, influences the development of anxious and depressive disorders. Stress responses are initiated via a pro-stress circuit in the anterior region of the basolateral amygdala (aBLA). This circuit contains pyramidal glutamatergic neurons that express genetic markers Camk2α, Rspo2, and Hcrtr1, which enhance stress-vulnerable behaviors via Orx₁R activity, and are inhibited directly by Orx₂R activation on Gad1, Hcrtr2, Cck GABAergic neurons. Our results have suggested stress circuitry in BLA is modulated by Orx₁R and Orx₂R activity, which counterbalance stress responsivity via Rspo2-positive glutamatergic neurons in aBLA, but whether these effects are consistent with systemic delivery is unknown. These receptor-dependent biases contribute to behavioral, physiological and molecular outcomes associated with psychiatric disorders, such as anxiety, depression, and post-traumatic stress disorder. Administration of a selective orexin receptor cross-over (SORCO; Orx₁R antagonist and Orx₂R agonist combination) treatment alleviates anxiogenic behavioral outputs in socially stressed mice, by decreasing escape latency in stress-vulnerable (Stay) mice (phenotypic reversal; vulnerable to resilient), and reducing the time spent freezing in response to the presence of a social aggressor (socially induced) in stress resilient (Escape) mice. Behavioral results coincided with a decrease in Rspo2 and an increase in Hcrtr2 gene expression in aBLA of SORCO-treated Stay mice, and an increase in Akt3 and mTOR transcription in Stay mice treated with an Orx₂R agonist (YNT-185). Our findings indicate that a combination of OrxR drugs (SORCO) provides potentially therapeutic outcomes through modifications of stress neurocircuitry, triggered by increasing expression of genes associated with neuroplasticity.