Differential effects of orexin system activation on dizocilpine-induced schizophrenia-like behaviors in mice

Schizophrenia encompasses positive, negative, and cognitive symptoms, and accumulating evidence suggests that the orexin system may modulate circuits relevant to these domains. Here, we investigated whether orexin-related interventions influence schizophrenia-like behaviors induced by the NMDA receptor antagonist dizocilpine in female and male mice. Two distinct approaches were used: nasal orexin A administration and chemogenetic activation of orexin neurons via DREADDs. Behavioral assessments included prepulse inhibition (PPI), locomotion and exploratory activity in the open field, social behavior, and working memory in the Y-maze. Overall, dizocilpine robustly induced schizophrenia-like phenotypes across these paradigms. Nasal orexin A exacerbated the dizocilpine-induced PPI deficit but attenuated the associated increase in startle reactivity, did not modify dizocilpine-induced hyperactivity, and partially rescued working memory impairments. Chemogenetic activation reproduced the PPI pattern observed with nasal orexin A, increased locomotion in both control- and dizocilpine-treated mice, induced anxiolytic-like effects in the open field, restored exploratory rearing, facilitated social recognition, and fully rescued working memory deficits. In some cases, the effects of these orexin-related interventions were differently pronounced in the two sexes. These findings indicate that activating the orexin system may worsen behavioral endophenotypes related to positive symptoms while alleviating those associated with negative and cognitive symptoms. However, substantial variability across assays, potentially related to the dosing of dizocilpine, orexin A, and CNO, as well as protocol-dependent constraints in some behavioral paradigms, limits definitive interpretation. Nevertheless, the present data reveal novel and domain-specific effects of orexin signaling in schizophrenia-relevant behavioral circuits and highlight the importance of exploring interventions with intermediate efficacy, including newly emerging orexin receptor agonists, to more precisely delineate orexin-dependent mechanisms and their therapeutic potential for negative and cognitive symptom domains.