Orexin/hypocretin receptor modulation of anxiolytic and antidepressive responses during social stress and decision-making: Potential for therapy

Hypothalmic orexin/hypocretin (Orx) neurons in the lateral and dorsomedial perifornical region (LH-DMH/PeF) innervate broadly throughout the brain, and receive similar inputs. This wide distribution, as well as two Orx peptides (Orx_A and Orx_B) and two Orx receptors (Orx₁ and Orx₂) allow for functionally related but distinctive behavioral outcomes, that include arousal, sleep-wake regulation, food seeking, metabolism, feeding, reward, addiction, and learning. These are all motivational functions, and tie the orexin systems to anxiety and depression as well. We present evidence, that for affective behavior, Orx₁ and Orx₂ receptors appear to have opposing functions. The majority of research on anxiety- and depression-related outcomes has focused on Orx₁ receptors, which appear to have primarily anxiogenic and pro-depressive actions. Although there is significant research suggesting contrary findings, the primary potential for pharmacotherapies linked to the Orx₁ receptor is via antagonists to block anxious and depressive behavior. Dual orexin receptor antagonists have been approved for treatment of sleep disorders, and are likely candidates for adaptation for affect disorder treatments. However, we present evidence here that demonstrates the Orx₂ receptors are anxiolytic and antidepressive. Using a new experimental pre-clinical model of anxious and depressive behavior stimulated by social stress and decision-making that produces two stable behavioral phenotypes, Escape/Resilient and Stay/Susceptible, we tested the effects of intracerebroventricular injections of Orx₂ agonist and antagonist drugs. Over ten behavioral measures, we have demonstrated that Orx₂ agonists promote resilience, as well as anxiolytic and antidepressive behavior. In contrast, Orx₂ antagonists or knockdown kindle anxious and pro-depressive behavior plus increase susceptibility. The results suggest that the Orx₂ receptor may be a useful target for pharmacotherapies to treat anxiety and depression.