Behavioral deficits and cellular damage following developmental ethanol exposure in rats are attenuated by CP-101,606, an NMDAR antagonist with unique NR2B specificity.
NMDAR-mediated excitotoxicity has been implicated in some of the impairments following fetal ethanol exposure. Previous studies suggest that both neuronal cell death and some of the behavioral deficits can be reduced by NMDAR antagonism during withdrawal, including antagonism of a subpopulation of receptors containing NR2B subunits. To further investigate NR2B involvement, we selected a compound, CP-101,606 (CP) which binds selectively to NR2B/2B stoichiometries, for both in vitro and in vivo analyses. For the in vitro study, hippocampal explants were exposed to ethanol for 10 days and then 24 h following removal of ethanol, cellular damage was quantified via propidium iodide fluorescence. In vitro ethanol withdrawal-associated neurotoxicity was prevented by CP (10 and 25 nM). In vivo ethanol exposure was administered on PNDs 1-7 with CP administered 21 h following cessation. Activity (PNDs 20-21), motor skills (PNDs 31-33), and maze navigation (PNDs 43-44) were all susceptible to ethanol insult; treatment with CP (15 mg/kg) rescued these deficits. Our findings show that CP-101,606, a drug that blocks the NR2B/2B receptor, can reduce some of the damaging effects of "3rd trimester" alcohol exposure in our rodent model. Further work is clearly warranted on the neuroprotective potential of this drug in the developing brain.
Dept. of Psychology, University of Kentucky, Lexington, KY 40506-0044, USA.
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B
Lewis
K A
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Wellmann
A M H
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Kehrberg
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ML
Carter
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Baldwin
M
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Cohen
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Barron
D020269:Alcoholic Neuropathy / Q000517:prevention & control*; D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000209:etiology / Q000517:prevention & control; D001522:Behavior, Animal / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D007859:Learning Disabilities / Q000209:etiology / Q000517:prevention & control; D008297:Male; D019957:Motor Skills Disorders / Q000209:etiology / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D018696:Neuroprotective Agents; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C095106:traxoprodil mesylate