Dose-dependent effects of chronic central infusion of oxytocin on anxiety, oxytocin receptor binding and stress-related parameters in mice

Abstract

Chronic psychosocial stress is a recognized risk factor for various affective and somatic disorders. In an established murine model of chronic psychosocial stress, exposure to chronic subordinate colony housing (CSC) results in an alteration of physiological, behavioral, neuroendocrine and immunological parameters, including a long-lasting increase in anxiety, adrenal hypertrophy and thymus atrophy. Based on the stress-protective and anxiolytic properties of oxytocin (OXT) after acute administration in rodents and humans, the major aims of our study were to assess whether chronic administration of OXT dose-dependently affects the behavior and physiology of male mice, as for therapeutic use in humans, mostly chronic treatment approaches will be used. Further, we studied, whether chronic administration during CSC prevents stress-induced consequences. Our results indicate that chronic intracerebroventricular (ICV) infusion of OXT (15 days) at high (10ng/h), but not at low (1ng/h) dose, induces an anxiogenic phenotype with a concomitant reduction of OXT receptor (OXTR) binding within the septum, the basolateral and medial amygdala, as well as the median raphe nucleus. Further, we demonstrate that chronic ICV infusion of OXT (1ng/h) during a 19-day CSC exposure prevents the hyper-anxiety, thymus atrophy, adrenal hypertrophy, and decreased in vitro adrenal ACTH sensitivity. Thus, given both negative, but also beneficial effects seen after chronic OXT treatment, which appear to be dose-dependent, a deeper understanding of long-lasting treatment effects is required before OXT can be considered for long-term therapeutic use for the treatment of psychopathologies such as autism, schizophrenia or anxiety-disorders.