Age-dependent effects of oxytocin on corticosterone-induced behavioral alterations and weight gain in male rats

Introduction

Chronic activation of the hypothalamic-pituitary-adrenal (HPA) axis during development leads to elevated corticosterone (CORT) levels, which are linked to obesity, and emotional dysregulation [1]. Oxytocin (OXY) receptors are widely distributed in brain regions governing energy balance and emotionality, suggesting that OXY plays a pivotal role in maintaining homeostasis [2,3]. However, the efficacy of OXY in mitigating the long-term effects of CORT across different postnatal development stages remains to be elucidated.

Aims

The primary objective of this study was to evaluate the age-dependent efficacy of oxytocin in correcting behavioral disturbances and metabolic shifts (body weight gain) induced by chronic corticosterone administration at different stages of rat postnatal development.

Methods

The study was conducted on male rats divided into four experimental groups. The control group received no CORT, while three experimental groups were subjected to daily intraperitoneal (IP) injections of corticosterone (20 mg/kg) during specific periods: PN10–40 (early postnatal), PN10–60 (mid-adolescence), and PN10–90 (late adolescence). These schedules were designed to model chronic stress at various maturation phases. Following the completion of the CORT protocol, a subset of rats from each group received daily IP injections of oxytocin (1 mg/kg) for 10 consecutive days. Behavioral activity was monitored in the Open Field. Body weight was measured at PN100 to assess long-term metabolic outcomes. Statistical analysis was performed using two-way ANOVA (Group × Period) followed by Tukey’s HSD post-hoc comparisons, with significance set at p < 0.05.

Results

In the PN10–40 group, CORT induced a significant anxiety-like phenotype, evidenced by a reduction in square crossings, center entries, and head-lifting (p < 0.01$), alongside increased grooming duration—an indicator of depressive-like states. Subsequent OXY administration (PN50–60) significantly reversed these behavioral deficits (p < 0.01), effectively restoring exploratory activity to near-control levels. In the PN10–60 and PN10–90 groups, OXY provided only partial behavioral recovery; the PN10–90 group exhibited severe hypoactivity and depression-like behavior that remained significantly lower than the norm despite OXY treatment.

Metabolically, chronic CORT led to substantial weight gain in the PN10–60 (+12.5%) and PN10–90 (+31.6%) groups. OXY treatment at PN10–60 significantly reduced weight from 320g to 280g (p < 0.05, a 12.5% decrease), likely by mitigating hyperphagia and visceral adiposis. In the PN10–90 group, OXY facilitated a weight reduction from 390g to 350g (-10.2%), but the rats remained significantly heavier than controls (p < 0.01). No significant weight shifts were observed in the PN10–40 group, suggesting that obesity develops primarily with longer-term exposure into late adolescence.

Conclusions

The therapeutic effectiveness of oxytocin is strictly dependent on the developmental window and the cumulative duration of CORT exposure. Early intervention appears decisive in preventing long-term behavioral and emotional dysregulation. While OXY demonstrates potent anxiolytic and anti-obesity properties by modulating the HPA axis, its capacity for complete metabolic and behavioral normalization diminishes as chronic stress extends into late adolescence. These findings underscore the importance of early-stage interventions to maintain homeostatic balance.

This research was funded by Shota Rustaveli National Science Foundation FR-24-401

References

1. Hayashida, S., Kuwaki, T., Ishii, H., 2021. Oxytocin improves HPA axis dysregulation and reduces anxiety-like behavior in prenatally stressed rats. Neurosci. Lett. 741, 135471.
2. Deblon, N., Veyrat-Durebex, C., Bourgoin, L., et al., 2011. Mechanisms of the anti-obesity effects of oxytocin in diet-induced obese rats. PLoS One 6 (9), e25565.
3. Petersson, M., Lundeberg, T., Uvnäs-Moberg, K., 1999. Short-term increase and long-term decrease of blood pressure in response to oxytocin-potentiating effect of female steroid hormones. J. Neuroendocrinol. 11 (2), 153-161.