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40 μg/kg OXA attenuates PPI% of non-sleep-deprived rats at 78 and 86 dB prepulse intensities.72-h REM sleep deprivation attenuates PPI% for all prepulse intensities.10 μg/kg OXA restores PPI% of sleep-deprived rats at 78 dB prepulse intensity.Startle response of non-sleep-deprived or sleep-deprived rats is not effected by OXA.OXA modulates PPI response, oppositely for non-sleep-deprived and sleep-deprived rats.Orexin is a novel neurotransmitter released from lateral hypothalamus, that is a crucial modulator in sleep/wakefulness system. Recent studies also suggest its possible role in the neurodevelopmental disorders, such as schizophrenia. Our study consists of two experiments, where we investigate the effect of orexin A (OXA), one of two isoforms of orexin that can pass blood brain barrier, on the prepulse inhibition of acoustic startle reflex. The first experiment tested the effect of OXA on PPI response of non-sleep-deprived rats via intraperitoneal injection 30 min before testing. Our results show that 40 μg/kg OXA attenuates PPI% at 78 dB and 86 dB prepulse intensities. The second experiment utilized 72-h REM sleep deprivation, as a model for sleep-deprivation-induced impairment of PPI response. Here, we tested the effect of OXA on PPI% of sleep-deprived rats via intraperitoneal injection at the last 30 min of sleep deprivation, testing for PPI immediately afterwards. Our results showed that (1) sleep deprivation attenuates the PPI% at 74 dB, 78 dB and 86 dB prepulse intensities and (2) 10 μg/kg OXA completely restores the impaired PPI% at 78 dB only, where the highest PPI% impairment was observed. These results suggest that orexin A modulates PPI response in rats in a dose-dependent manner, oppositely for non-sleep-deprived and sleep-deprived rats, and a more detailed investigation for the etiology of this effect should follow.