Neurophysiological and neuropharmacological effects of melatonin MT2 receptors activation in MK-801-induced schizophrenia-like dysfunctions

Schizophrenia (SCZ) is a chronic psychiatric disorder characterized by positive, negative, and cognitive symptoms that remain insufficiently controlled by current dopamine- and serotonin-based antipsychotics. Emerging evidence implicates melatonin MT2 receptors in the regulation of the sleep-wake cycle, circadian rhythms and cortical inhibition, both altered in SCZ. Here, we investigated the neuropharmacological effects of the selective MT2 partial agonist UCM924 in the MK-801 model of SCZ-like dysfunctions in male mice. UCM924 (10 mg/kg, intraperitoneally) was selected as a dose not affecting basal locomotion. Acute administration of MK-801 (0.3 mg/kg) induced hyperlocomotion, social interaction abnormalities, and impaired spatial working memory. UCM924 normalized MK-801-induced hyperactivity and social deficits but did not improve cognitive performance. Immunofluorescence analysis revealed that UCM924 increased c-Fos activation in parvalbumin-positive interneurons of the prefrontal cortex, with no effect on tyrosine hydroxylase-positive neurons in the ventral tegmental area. Local field potential recordings showed that UCM924 alone reduced gamma-band power (12-90 Hz) in both regions, whereas MK-801 markedly enhanced it. Co-administration of MK-801 and UCM924 resulted in MK-801-dominant oscillatory patterns, suggesting limited efficacy of MT2 activation in restoring network synchronization. These findings indicate that MT2 receptor stimulation selectively enhances prefrontal inhibitory tone and ameliorates behavioral abnormalities related to positive-like and negative-like symptoms, without normalizing cognitive and electrophysiological deficits. Overall, MT2 receptor-selective drugs may represent promising candidates for targeting specific symptom domains in SCZ through mechanisms distinct from current antipsychotics.