The Effects of Intranasal Orexin-A on Mk-801-Induced Attentional Deficits: Addressing Cognitive Impairment in An Nmda Receptor Hypofunction Model of Schizophrenia
Master of Arts (M.A.)
Joshua A. Burk
Joshua A. Burk
Pamela S. Hunt
Jennifer A. Stevens
Schizophrenia (SZ) is a debilitating condition wherein those afflicted experience positive symptoms, including hallucinations and delusions, as well as negative symptoms, including alterations of processing affecting cognition and social interactions. The NMDA receptor hypofunction model of SZ asserts that a reduction in hippocampal NMDA receptor input produces the pathology of this disorder, promoting excessive frontocortical excitatory neurotransmission – particularly overstimulation of basal forebrain cholinergic neurons – that ultimately impairs cognitive and sensorimotor processes. Orexin-A (OxA), a neuropeptide principally involved in wakefulness and appetitive behaviors, has been shown to demonstrate cognitive-enhancing qualities in models of psychiatric and neurodegenerative illness. In the present study, the effects of OxA on attentional performance were examined in a NMDA receptor antagonist model of SZ. Male Fischer 344 Brown Norway F1 Hybrid rats (N = 12) received both intraperitoneal injections of MK-801 and intranasal administration of OxA prior to placement in a sustained attention task requiring differentiation between signal trials (500, 100, and 25ms illumination of a central panel light) and non-signal trials (no light illumination). Overall, it was shown that the highest dose of OxA exacerbated MK-801-induced attentional deficits. While the small OxA concentration slightly protected against impairments in the correct rejection of the signal and increased omission rates at the low dose of MK-801, this excitatory neuromodulator was largely unable to improve performance in the attention task. These findings suggest that, in a state of cortical hyperexcitation like what is observed both in SZ and following NMDA receptor antagonism, the introduction of pharmacotherapies augmenting activity at the orexinergic system further exacerbates existing cognitive dysfunction in lieu of alleviating these symptoms.
© The Author
Maness, Eden Blake-Lea, "The Effects of Intranasal Orexin-A on Mk-801-Induced Attentional Deficits: Addressing Cognitive Impairment in An Nmda Receptor Hypofunction Model of Schizophrenia" (2017). Dissertations, Theses, and Masters Projects. William & Mary. Paper 1530192333.