310. Melatonin MT2 receptors activation attenuates MK-801-induced schizophrenia-like effects

Abstract

Abstract Background Schizophrenia (SCZ) is a chronic psychiatric disorder characterized by positive, negative, and cognitive symptoms that remain insufficiently addressed by existing dopamine- and serotonin-based antipsychotics. Emerging evidence implicates melatonin MT2 receptors in the regulation of circadian rhythms and cortical inhibitory tone, both profoundly altered in SCZ. Together, these findings highlight MT2 receptors as an underexplored but promising therapeutic entry point. Aims & Objectives This study investigated whether selective MT2 receptor activation by the partial agonist UCM924 can counteract the behavioral, cellular, and electrophysiological alterations induced by MK-801, a well-established pharmacological model of SCZ-like dysfunctions. Method To induce SCZ-like symptoms, we used MK-801, a non-competitive NMDA receptor antagonist whose mechanism aligns with glutamatergic dysfunction implicated in SCZ [5]. Male mice received MK-801 (0.3 mg/kg), UCM924 (10 mg/kg, i.p.), or their combination. Locomotor activity, social interaction, and spatial working memory were assessed using standard behavioral paradigms. Immunofluorescence quantified c-Fos activation of parvalbumin-positive (PV+) interneurons of the pre-frontal cortex and in tyrosine hydroxylase-positive (TH+) neurons of the ventral tegmental area. Lastly, local field potential (LFP) recordings from both regions were analyzed to evaluate to investigate task-related neural oscillations during a 5-min open-field session. Results MK-801 induced robust hyperlocomotion, social deficits, and impaired working memory. UCM924 selectively rescued MK-801–induced hyperactivity and social behavior but did not ameliorate cognitive impairment. At the cellular level, UCM924 increased c-Fos expression in prefrontal PV+ interneurons while leaving dopaminergic neuron activation unchanged. LFP recording showed that UCM924 alone reduces gamma-band power, whereas MK-801 markedly enhances it. Under co-administration, network oscillations remained dominated by MK-801, highlighting the limited capacity of MT2 activation to restore gamma synchrony. Discussion & Conclusions These findings indicate that MT2 receptor stimulation selectively enhances prefrontal inhibitory circuitry and ameliorates behavioral domains relevant to positive-like and negative-like symptoms of SCZ. Although cognitive and electrophysiological abnormalities were not normalized, UCM924 engages mechanisms clearly distinct from conventional antipsychotics, underscoring MT2 receptors as a potential targets for domain-specific therapeutic strategies. By modulating inhibitory interneuron function rather than dopaminergic pathways, MT2-selective agents may provide innovative avenues for symptom dimensions that remain insufficiently addressed by current treatments.