Age-Related Effects of Exogenous Melatonin on Anxiety-like Behavior in C57/B6J Mice

The synthesis of melatonin (MLT) physiologically decreases during aging. Treatment with MLT has shown anxiolytic, hypnotic, and analgesic effects, but little is known about possible age-dependent differences in its efficacy. Therefore, we studied the effects of MLT (20 mg/kg, intraperitoneal) on anxiety-like behavior (open field (OFT), elevated plus maze (EPMT), three-chamber sociability, and marble-burying (MBT) tests), and the medial prefrontal cortex (mPFC)-dorsal hippocampus (dHippo) circuit in adolescent (35-40 days old) and adult (three-five months old) C57BL/6 male mice. MLT did not show any effect in adolescents in the OFT and EPMT. In adults, compared to vehicles, it decreased locomotor activity and time spent in the center of the arena in the OFT and time spent in the open arms in the EPMT. In the MBT, no MLT effects were observed in both age groups. In the three-chamber sociability test, MLT decreased sociability and social novelty in adults, while it increased sociability in adolescents. Using local field potential recordings, we found higher mPFC-dHippo synchronization in the delta and low-theta frequency ranges in adults but not in adolescents after MLT treatment. Here, we show age-dependent differences in the effects of MLT in anxiety paradigms and in the modulation of the mPFC-dHippo circuit, indicating that when investigating the pharmacology of the MLT system, age can significantly impact the study outcomes.

Automated summary

The synthesis of melatonin decreases with age. While high dose treatment with melatonin has shown anxiolytic, hypnotic, and analgesic effects, little is known about its efficacy in different age groups. This study investigated the effects of melatonin on anxiety-like behavior and the mPFC-dHippo circuit in adolescent and adult mice. The results showed age-dependent differences in the effects of melatonin and its modulation of the mPFC-dHippo circuit, emphasizing the importance of considering age in the study of the pharmacology of melatonin.