Effects of the cognition-enhancing agent ABT-239 on fetal ethanol-induced deficits in dentate gyrus synaptic plasticity

J Pharmacol Exp Ther. 2010 Jul;334(1):191-8. doi: 10.1124/jpet.109.165027. Epub 2010 Mar 22.

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 H(3) 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 H(3) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking / adverse effects
  • Animals
  • Benzofurans / administration & dosage
  • Benzofurans / therapeutic use*
  • Dentate Gyrus / drug effects*
  • Dentate Gyrus / embryology
  • Dentate Gyrus / metabolism
  • Electrophysiological Phenomena
  • Ethanol / blood
  • Ethanol / toxicity*
  • Female
  • Fetal Development / drug effects*
  • Histamine H3 Antagonists / administration & dosage
  • Histamine H3 Antagonists / therapeutic use*
  • Long-Term Potentiation / drug effects*
  • Male
  • Maternal Exposure / adverse effects
  • Nootropic Agents / administration & dosage
  • Nootropic Agents / therapeutic use*
  • Pregnancy
  • Prenatal Exposure Delayed Effects / chemically induced
  • Prenatal Exposure Delayed Effects / physiopathology
  • Prenatal Exposure Delayed Effects / prevention & control*
  • Pyrrolidines / administration & dosage
  • Pyrrolidines / therapeutic use*
  • Rats
  • Rats, Long-Evans
  • Rats, Sprague-Dawley
  • Species Specificity

Substances

  • Benzofurans
  • Histamine H3 Antagonists
  • Nootropic Agents
  • Pyrrolidines
  • Ethanol
  • benzonitrile, 4-(2-(2-((2r)-2-methyl-1-pyrrolidinyl)ethyl)-5-benzofuranyl)-