Sharma_2025_Life.Sci__123978

CUS disrupts brain cellular and molecular physiology, leading to neurotransmitter and neuroendocrine dysregulation, resulting in neurobehavioral changes like anxiety, depression, and cognitive impairment. Numerous neurobiological pathways regulating neurotransmitter systems, are implicated in mood regulation and stress response, notably the TAAR1 receptor have been documented to play a major role in neuropshychiatric diseases. This research investigates CREB-dependent neurobehavioral alterations via TAAR1 receptor modulation with RO5256390 in Chronic Unpredictable Stress Model. For evaluating the impact of CUS and pharmacological interventions on neurobehavioral changes, Swiss albino mice of either sex were subjected to various stressors for 8 weeks. The behavioral traits for anxiety, depression and memory impairment were assessed by EPM, SPT, TST and MWM. The level of corticosterone dopamine, serotonin; biochemical parameters of oxidative stress, inflammatory mediators; acetylcholinesterase (AChE) activity and histological changes in hippocampus and cortex were also examined. Administration of RO5256390 (0.5, 1 and 2 mg/kg i.p), improved behavioral and biochemical parameters in CUS-exposed mice, most likely, by modulating the activity of TAAR1. Fluoxetine (20 mg/kg, p.o) was employed as a standard reference drug in CUS induced mice to facilitate clinical comparison. It was also observed that neuroprotective effects of RO5256390 were significantly abolished by pre-treatment with 666-15 (10 mg/kg, i.p.), a CREB inhibitor, which signifies the involvement of CREB signaling in attenuating the protective mechanism of RO5256390. Therefore, this study highlights the critical role of TAAR1-CREB pathway in neuroprotection and therapeutic potential of RO5256390 in alleviating neurobehavioral changes associated with CUS.