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Norepinephrine transporter blockade can normalize the prepulse inhibition deficits found in dopamine transporter knockout mice.
Neuropsychopharmacology. 2006 Oct; 31(10):2132-9.N

Abstract

Dopamine transporter knockout (DAT KO) mice display deficits in sensorimotor gating that are manifested by reduced prepulse inhibition (PPI) of the acoustic startle reflex. Since PPI deficits may model some of the cognitive dysfunctions identified in certain neuropsychiatric patients, we have studied the effects of transporter blockers on PPI in wild-type and DAT KO mice. Treatments with High dose psychostimulants that block DAT as well as the norepinephrine (NET) and serotonin (SERT) transporters (60 mg/kg cocaine or methylphenidate) significantly impaired PPI in wild-type mice. By contrast, these treatments significantly ameliorated the PPI deficits observed in untreated DAT KO mice. In studies with more selective transport inhibitors, the selective NET inhibitor nisoxetine (10 or 30 mg/kg) also significantly reversed PPI deficits in DAT KO mice. By contrast, while the SERT inhibitor fluoxetine (30 mg/kg) normalized these PPI deficits in DAT KO mice, citalopram (30 or 100 mg/kg) failed to do so. The 'paradoxical' effects of cocaine and methylphenidate in DAT KO mice are thus likely to be mediated, at least in part by the ability of these drugs to block NET, although serotonin systems may also have some role. Together with recent microdialysis data, these results support the hypothesis that prefrontal cortical NET blockade and consequent enhancement of prefrontal cortical extracellular dopamine mediates the reversal of PPI deficits in DAT KO mice.

Authors+Show Affiliations

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

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16407898

Citation

Yamashita, Motoyasu, et al. "Norepinephrine Transporter Blockade Can Normalize the Prepulse Inhibition Deficits Found in Dopamine Transporter Knockout Mice." Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, vol. 31, no. 10, 2006, pp. 2132-9.
Yamashita M, Fukushima S, Shen HW, et al. Norepinephrine transporter blockade can normalize the prepulse inhibition deficits found in dopamine transporter knockout mice. Neuropsychopharmacology. 2006;31(10):2132-9.
Yamashita, M., Fukushima, S., Shen, H. W., Hall, F. S., Uhl, G. R., Numachi, Y., Kobayashi, H., & Sora, I. (2006). Norepinephrine transporter blockade can normalize the prepulse inhibition deficits found in dopamine transporter knockout mice. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 31(10), 2132-9.
Yamashita M, et al. Norepinephrine Transporter Blockade Can Normalize the Prepulse Inhibition Deficits Found in Dopamine Transporter Knockout Mice. Neuropsychopharmacology. 2006;31(10):2132-9. PubMed PMID: 16407898.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Norepinephrine transporter blockade can normalize the prepulse inhibition deficits found in dopamine transporter knockout mice. AU - Yamashita,Motoyasu, AU - Fukushima,Setsu, AU - Shen,Hao-wei, AU - Hall,F Scott, AU - Uhl,George R, AU - Numachi,Yohtaro, AU - Kobayashi,Hideaki, AU - Sora,Ichiro, Y1 - 2006/01/11/ PY - 2006/1/13/pubmed PY - 2006/11/2/medline PY - 2006/1/13/entrez SP - 2132 EP - 9 JF - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JO - Neuropsychopharmacology VL - 31 IS - 10 N2 - Dopamine transporter knockout (DAT KO) mice display deficits in sensorimotor gating that are manifested by reduced prepulse inhibition (PPI) of the acoustic startle reflex. Since PPI deficits may model some of the cognitive dysfunctions identified in certain neuropsychiatric patients, we have studied the effects of transporter blockers on PPI in wild-type and DAT KO mice. Treatments with High dose psychostimulants that block DAT as well as the norepinephrine (NET) and serotonin (SERT) transporters (60 mg/kg cocaine or methylphenidate) significantly impaired PPI in wild-type mice. By contrast, these treatments significantly ameliorated the PPI deficits observed in untreated DAT KO mice. In studies with more selective transport inhibitors, the selective NET inhibitor nisoxetine (10 or 30 mg/kg) also significantly reversed PPI deficits in DAT KO mice. By contrast, while the SERT inhibitor fluoxetine (30 mg/kg) normalized these PPI deficits in DAT KO mice, citalopram (30 or 100 mg/kg) failed to do so. The 'paradoxical' effects of cocaine and methylphenidate in DAT KO mice are thus likely to be mediated, at least in part by the ability of these drugs to block NET, although serotonin systems may also have some role. Together with recent microdialysis data, these results support the hypothesis that prefrontal cortical NET blockade and consequent enhancement of prefrontal cortical extracellular dopamine mediates the reversal of PPI deficits in DAT KO mice. SN - 0893-133X UR - https://www.unboundmedicine.com/medline/citation/16407898/Norepinephrine_transporter_blockade_can_normalize_the_prepulse_inhibition_deficits_found_in_dopamine_transporter_knockout_mice_ DB - PRIME DP - Unbound Medicine ER -