Norepinephrine transporter blockade can normalize the prepulse inhibition deficits found in dopamine transporter knockout mice.
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.
Yamashita
Motoyasu
M
Department of Psychobiology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
Fukushima
Setsu
S
Shen
Hao-wei
HW
Hall
F Scott
FS
Uhl
George R
GR
Numachi
Yohtaro
Y
Kobayashi
Hideaki
H
Sora
Ichiro
I
D000161:Acoustic Stimulation / Q000379:methods; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D015283:Citalopram / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000172:deficiency*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology; D007266:Inhibition, Psychological; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000502:physiology*; D011930:Reaction Time / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D000697:Central Nervous System Stimulants; D015283:Citalopram; D003042:Cocaine; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D005473:Fluoxetine; D008774:Methylphenidate; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C011386:nisoxetine