Abstract
Prepulse inhibition (PPI) deficits are among the most reproducible phenotypic markers found in schizophrenic patients. We recently reported that nisoxetine, a selective norepinephrine transporter (NET) inhibitor, reversed the PPI deficits that have been identified in dopamine transporter (DAT) knockout (KO) mice. However, the mechanisms underlying nisoxetine-induced PPI recovery in DAT KO mice were unclear in previous experiments. To clarify these mechanisms, PPI was tested after microinjections of nisoxetine into the medial prefrontal cortex (mPFc) or nucleus accumbens (NAc) in wildtype (WT) and DAT KO mice. c-Fos immunohistochemistry provided an indicator of neural activation. Multiple-fluorescent-labeling procedures and the retrograde tracer fluorogold were employed to identify nisoxetine-activated neurons and circuits. Systemic nisoxetine activated the mPFc, the NAc shell, the basolateral amygdala, and the subiculum. Infusions of nisoxetine into the mPFc reversed PPI deficits in DAT KO mice, but produced no changes in WT mice, while infusion of nisoxetine into the NAc had no effect on PPI in both WT and DAT KO mice. Experiments using multiple-fluorescent labeling/fluorogold revealed that nisoxetine activates presumed glutamatergic pyramidal cells that project from the mPFc to the NAc. Activated glutamatergic projections from the mPFc to the NAc appear to have substantial roles in the ability of a NET inhibitor to normalize PPI deficits in DAT KO. Thus, this data suggest that selective NET inhibitors such as nisoxetine might improve information processing deficits in schizophrenia via regulation of cortico-subcortical neuromodulation.
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Acknowledgements
We thank Dr Takeshi Kaneko for the gift of PAG monoclonal antibody, Nozomi Okayasu for technical assistance, and Dr Taku Sato and Dr Shiho Miyazawa for assistance with statistical analysis. This work was supported in part by Scientific Research on Priority Areas-System study on higher-order brain functions and Research on Pathomechanisms of Brain Disorders, Core Research for Evolutional Science and Technology (CREST) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Global COE Program (Basic and Translational Research Center for Global Brain Science), MEXT, Japan, and through funding from the Intramural Research Program of the National Institute on Drug Abuse, NIH/DHHS, USA (GRU and FSH).
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Arime, Y., Kasahara, Y., Hall, F. et al. Cortico-Subcortical Neuromodulation Involved in the Amelioration of Prepulse Inhibition Deficits in Dopamine Transporter Knockout Mice. Neuropsychopharmacol 37, 2522–2530 (2012). https://doi.org/10.1038/npp.2012.114
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DOI: https://doi.org/10.1038/npp.2012.114
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