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

Presentation_1_Sex-dependent effects of the uncompetitive N-methyl-D-aspartate receptor antagonist REL-1017 in G93A-SOD1 amyotrophic lateral sclerosis mice.PPTX

IntroductionThe pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease caused by the demise of motor neurons has been linked to excitotoxicity caused by excessive calcium influx via N-methyl-D-aspartate receptors (NMDARs), suggesting that uncompetitive NMDAR antagonism could be a strategy to attenuate motor neuron degeneration. REL-1017, the dextro-isomer of racemic methadone, is a low-affinity uncompetitive NMDAR antagonist. Importantly, in humans REL-1017 has shown excellent tolerability in clinical trials for major depression.MethodsHere, we tested if REL-1017 improves the disease phenotypes in the G93A SOD1 mouse, a well-established model of familial ALS, by examining survival and motor functions, as well as the expression of genes and proteins involved in neuroplasticity.ResultsWe found a sex-dependent effect of REL-1017 in G93A SOD1 mice. A delay of ALS symptom onset, assessed as 10%-decrease of body weight (p ConclusionIn conclusion, this study provides preclinical in vivo evidence supporting the clinical evaluation of REL-1017 in ALS.</p