Abstract
Prenatal ethanol exposure causes deficits in hippocampal synaptic plasticity and learning. At present, there are no clinically effective pharmacotherapeutic interventions for these deficits. In this study, we examined whether the cognition-enhancing agent 4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl) benzonitrile (ABT-239), a histamine H3 receptor antagonist, could ameliorate fetal ethanol-induced long-term potentiation (LTP) deficits. Long-Evans rat dams consumed a mean of 2.82 g/kg ethanol during a 4-h period each day. This voluntary drinking pattern produced a mean peak serum ethanol level of 84 mg/dl. Maternal weight gain, offspring litter size, and birth weights were not different between ethanol-consuming and control groups. A stimulating electrode was implanted in the entorhinal cortical perforant path, and a recording electrode was implanted in the dorsal dentate gyrus of urethane-anesthetized adult male offspring. Baseline input/output responses were not affected either by prenatal ethanol exposure or by 1 mg/kg ABT-239 administered 2 h before data collection. No differences were observed between prenatal treatment groups when a 10-tetanus train protocol was used to elicit LTP. However, LTP elicited by 3 tetanizing trains was markedly impaired by prenatal ethanol exposure compared with control. This fetal ethanol-induced LTP deficit was reversed by ABT-239. In contrast, ABT-239 did not enhance LTP in control offspring using the 3-tetanus train protocol. These results suggest that histamine H3 receptor antagonists may have utility for treating fetal ethanol-associated synaptic plasticity and learning deficits. Furthermore, the differential effect of ABT-239 in fetal alcohol offspring compared with controls raises questions about the impact of fetal ethanol exposure on histaminergic modulation of excitatory neurotransmission in affected offspring.
Footnotes
This work was supported in part by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grants AA016619, AA017068]; and by dedicated research funds from the University of New Mexico Health Sciences Center.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.165027.
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ABBREVIATIONS:
- NDMA
- N-methyl-d-aspartate
- ABT-239
- 4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile
- mGluR
- metabotropic glutamate receptor
- LTP
- long-term potentiation
- PS
- population spike
- ES40
- stimulus intensity sufficient to generate 40% of maximal population spike response
- HFS
- high-frequency stimulation
- fEPSP
- fast excitatory postsynaptic potential slope
- ANOVA
- analysis of variance
- AMPA
- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.
- Received December 22, 2009.
- Accepted March 19, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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