EFFECTS OF ATOMOXETINE ON THE MPFC OF SHRSP/EZO AS AN ADHD ANIMAL MODEL

Abstract Background Attention-deficit/hyperactivity disorder (ADHD) is one of neurodevelopmental disorders, with inattention, hyperactivity, and impulsivity. At present, many treatment guidelines for ADHD list psychostimulants, such as methylphenidate and amphetamine, as first-line drugs for ADHD. Meanwhile, atomoxetine (ATX), a selective inhibitor of noradrenaline (NA) transport, has been developed as a nonstimulant that was approved for the treatment of ADHD, and is expected as an alternative to psychostimulants. We have previously reported that stroke-prone spontaneously hypertensive rats (SHRSP/Ezo) have the high validity of an ADHD animal model (Ueno et al., 2002; Hiraide et al., 2013). In rats, the medial prefrontal cortex (mPFC) is thought to correspond to the human frontal cortex which is a responsible brain region for cognitive function such as attention and impulsivity. We also reported the physiological dysfunction in the mPFC of SHRSP/Ezo (Shikanai et al., 2018; Shindo et al., 2022). Aims & Objectives In this study, we investigated effects of ATX on ADHD-like behaviors of SHRSP/Ezo and those mechanisms in the mPFC via monoamine transporters. Method Male SHRSP/Ezo and Wistar Kyoto/Ezo (WKY/Ezo, genetic control) rats were bred in our laboratory. We used 6-week-old animals for the behavioral evaluation and in vivo microdialysis. ATX was intraperitoneally administered 30 min before behavioral tests. We addressed the effect of ATX on the failure of LTP formation in the mPFC of SHRSP/Ezo using an electrophysiological method. Moreover, NA transporter protein expression levels was quantified by western blotting. All procedures were performed in accordance with the Guidelines for the Care and Use of Laboratory Animals of the Health Sciences University of Hokkaido. Results In behavioral experiments, ATX administration remarkably reduced motor hyperactivity of SHRSP/Ezo in the open-field test. Moreover, ATX improved inattentive behavior in the Y-maze test and impulsive-like behavior in the elevated plus-maze test in SHRSP/Ezo. In vivo microdialysis studies, ATX induced the increase of extracellular levels of both NA and dopamine (DA) in the mPFC of SHRSP/Ezo, but not serotonin. The failure of LTP formation in the mPFC of SHRSP/Ezo was ameliorated by systemic administration of ATX. In western blotting test, NA transporter protein expression level in the mPFC of SHRSP/Ezo was significantly higher than that of WKY/Ezo. Discussion and Conclusion The present study addressed effects of ATX on the mPFC of SHRSP/Ezo as an ADHD model rat. These findings suggested that ADHD-like behaviors observed in SHRSP/Ezo might be caused by abundant expression of NA transporter in the mPFC, and provided novel insights into the pathogenesis of ADHD. Furthermore, ameliorating effects of ATX for ADHD-like behaviors of SHRSP/Ezo could be due to elevation of both extracellular NA and DA, suggesting that new treatment strategies for ADHD may need the increase of multiple monoamine release. References 1)Ueno, K. I., Togashi, H., Mori, K., Matsumoto, M., Ohashi, S., Hoshino, A., Fujita, T., Saito, H., Minami, M.,&Yoshioka, M. (2002). Behavioural and pharmacological relevance of stroke-prone spontaneously hypertensive rats as an animal model of a developmental disorder. Behavioural pharmacology, 13(1), 1–13. https://doi.org/10.1097/00008877-200202000-00001 2)Hiraide, S., Ueno, K., Yamaguchi, T., Matsumoto, M., Yanagawa, Y., Yoshioka, M., &Togashi, H. (2013). Behavioural effects of monoamine reuptake inhibitors on symptomatic domains in an animal model of attention-deficit/hyperactivity disorder. Pharmacology, biochemistry, and behavior, 105, 89–97. https://doi.org/10.1016/j.pbb.2013.01.009 3)Shikanai, H., Oshima, N., Kawashima, H., Kimura, S. I., Hiraide, S., Togashi, H., Iizuka, K., Ohkura, K., &Izumi, T. (2018). N-methyl-d-aspartate receptor dysfunction in the prefrontal cortex of stroke-prone spontaneously hypertensive rat/Ezo as a rat model of attention deficit/hyperactivity disorder. Neuropsychopharmacology reports, 38(2), 61–66. https://doi.org/10.1002/npr2.12007 4)Shindo, T., Shikanai, H., Watarai, A., Hiraide, S., Iizuka, K., &Izumi, T. (2022). D-serine metabolism in the medial prefrontal cortex, but not the hippocampus, is involved in AD/HD-like behaviors in SHRSP/Ezo. European journal of pharmacology, 923, 174930. https://doi.org/10.1016/j.ejphar.2022.174930