[Abstract Title]. - Society for Neuroscience

Program#/Poster#: 293.10/SS38
Topic: C.15.d. Schizophrenia: Mutant animal models
Support: Grants-in-Aid from MECSST
Health Sciences Research Grants from MHLW
Title: Prefrontal NET blockade ameliorates prepulse inhibition deficits in dopamine transporter
knockout mice: involvement of cortical-subcortical pathways
Authors: *Y. ARIME 1 , F. S. HALL 2 , G. R. UHL 2 , I. SORA 1 ;
1 Dept of Biol. Psychiatry, Tohoku Univ., Sendai, Japan; 2 NIDA-IRP, Baltimore, MD
Abstract: Dopamine transporter knockout (DAT KO) mice exhibit hyperdopaminergic tone in
striatum (CPu) and nucleus accumbens (NAc) and normal dopamine levels in medial prefrontal
cortex (mPFc). DAT KO mice have deficits in prepulse inhibition (PPI) that are also
reproducibly identified in patients with neuropsychiatric disorders that include schizophrenia.
Selective norepinephrine transporter (NET) blockers are approved for treating ADHD and are
being considered for treating cognitive dysfunction in schizophrenics. We have recently reported
that the selective NET blocker nisoxetine reverses PPI deficits in DAT KO mice. To elucidate
the anatomical substrates that might underlie this recovery of PPI in these mice, we have
examined the region-specific effects of nisoxetine on PPI deficits in DAT KO mice. We have
compared results of systemic and local injections of nisoxetine on PPI, extracellular dopamine
levels and on expression of the activation marker c-Fos in neuronal populations labeled by
neuronal markers and the retrograde neuron tracer fluorogold. Systemic administration of
nisoxetine doses that normalize PPI defects in DAT KO mice increase the number of c-Fos
positive cells in mPFc, orbitofrontal cortex, NAc shell, basolateral amygdala and ventral
tegmental area. mPFc infusions of nisoxetine increased PPI in DAT KO mice. By contrast, NAc
infusions had no effect on PPI in either wildtype (WT) or DAT KO mice. Studies using labeling
with c-Fos antibodies, neuronal markers and fluorogold revealed that nisoxetine selectively
activates mPFc glutamatergic pyramidal neurons that project to NAc. Administration of
nisoxetine also increased extracellular dopamine levels in mPFc, consistent with a substantial
role for NET in accumulating dopamine in this brain region. These results suggest that alteration
of glutamatergic neurotransmission from mPFc to NAc underlies at least a portion of the ability
of nisoxetine to ameliorate PPI defects found in DAT KO mice.
Disclosures: Y. Arime, Health Sciences Research Grants from MHLW, B. Research Grant
(principal investigator, collaborator or consultant and pending grants as well as grants already
received); Grants-in-Aid from MECSST, B. Research Grant (principal investigator, collaborator
or consultant and pending grants as well as grants already received); F.S. Hall, NIDA-IRP,
NIH/DHHS, B. Research Grant (principal investigator, collaborator or consultant and pending
grants as well as grants already received); G.R. Uhl, NIDA-IRP, NIH/DHHS, B. Research Grant
(principal investigator, collaborator or consultant and pending grants as well as grants already
received); I. Sora, Grants-in-Aid from MECSST, B. Research Grant (principal investigator,
collaborator or consultant and pending grants as well as grants already received); Health