Abstract Introduction Dysregulated sleep and cognitive impairments are commonly reported in individuals with psychotic disorders, including schizophrenia (SZ) and bipolar disorder (BPD). Emerging evidence implicates the kynurenine pathway (KP) of tryptophan catabolism in the pathophysiology of psychotic disorders. Kynurenic acid (KYNA), a KP metabolite synthetized by kynurenine aminotransferases (KATs) from its biological precursor kynurenine, is elevated in brain tissue and the cerebrospinal fluid of patients with SZ and BPD. KYNA is hypothesized to play a key role in sleep disturbances, thus, we presently investigate if pharmacological inhibition of KAT II to reduce brain KYNA formation may overcome sleep. Methods We employed the embryonic kynurenine (EKyn) paradigm to induce KYNA elevation in the fetal brain (Pocivavsek et al 2014 Psychopharm). Wistar dams were fed either kynurenine (100 mg/day) (EKyn) or control wet mash (ECon) from embryonic day (ED) 15 to ED 22. Adult (postnatal day 56-85) male and female offspring were used in sleep studies (EEG/EMG telemetry) to evaluate the effectiveness of PF-04859989 (30 mg/kg, s.c.), an irreversible KAT II inhibitor. Each subject was treated at zeitgeber time (ZT) 0 with either vehicle or PF-04859989 and rapid-eye movement (REM) sleep, non-REM (NREM) sleep, and wakefulness parameters were assessed. Results KAT II inhibition significantly increased REM duration during the second half of the light phase in both male (P<0.01) and female (P<0.05) EKyn compared to vehicle treatment. PF-04859989 increased NREM duration and reduced wakefulness during the latter part of the dark phase in both ECon and EKyn male rats, accompanied with significant decrease in relative cage activity, but no differences were determined in female rats across 24 hr. Light phase analysis of spectral power during NREM sleep in EKyn rats revealed significant frequency by treatment interaction (P<0.0001) in males only, with enhanced delta power (0-4 Hz) after PF-04859989 treatment. Conclusion Acute decrease in brain KYNA mitigates sleep deficits and elicits higher quality sleep in male EKyn offspring, suggesting KAT II inhibition as a novel mechanistic approach to treating sleep deficiencies in a translationally-relevant preclinical paradigm. Support (If Any) This work was funded by National Institutes of Health Grant Nos. NIH R01 NS102209 & P50 MH103222.
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