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Cortico-subcortical neuromodulation involved in the amelioration of prepulse inhibition deficits in dopamine transporter knockout mice.
Neuropsychopharmacology. 2012 Oct; 37(11):2522-30.N

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.

Authors+Show Affiliations

Department of Biological Psychiatry, Tohoku University Graduate School of Medicine, Sendai, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22781838

Citation

Arime, Yosefu, et al. "Cortico-subcortical Neuromodulation Involved in the Amelioration of Prepulse Inhibition Deficits in Dopamine Transporter Knockout Mice." Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, vol. 37, no. 11, 2012, pp. 2522-30.
Arime Y, Kasahara Y, Hall FS, et al. Cortico-subcortical neuromodulation involved in the amelioration of prepulse inhibition deficits in dopamine transporter knockout mice. Neuropsychopharmacology. 2012;37(11):2522-30.
Arime, Y., Kasahara, Y., Hall, F. S., Uhl, G. R., & Sora, I. (2012). Cortico-subcortical neuromodulation involved in the amelioration of prepulse inhibition deficits in dopamine transporter knockout mice. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 37(11), 2522-30. https://doi.org/10.1038/npp.2012.114
Arime Y, et al. Cortico-subcortical Neuromodulation Involved in the Amelioration of Prepulse Inhibition Deficits in Dopamine Transporter Knockout Mice. Neuropsychopharmacology. 2012;37(11):2522-30. PubMed PMID: 22781838.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cortico-subcortical neuromodulation involved in the amelioration of prepulse inhibition deficits in dopamine transporter knockout mice. AU - Arime,Yosefu, AU - Kasahara,Yoshiyuki, AU - Hall,F Scott, AU - Uhl,George R, AU - Sora,Ichiro, Y1 - 2012/07/11/ PY - 2012/7/12/entrez PY - 2012/7/12/pubmed PY - 2013/2/27/medline SP - 2522 EP - 30 JF - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JO - Neuropsychopharmacology VL - 37 IS - 11 N2 - 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. SN - 1740-634X UR - https://www.unboundmedicine.com/medline/citation/22781838/Cortico_subcortical_neuromodulation_involved_in_the_amelioration_of_prepulse_inhibition_deficits_in_dopamine_transporter_knockout_mice_ L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22781838/ DB - PRIME DP - Unbound Medicine ER -