Effects of a novel cognition-enhancing agent on fetal ethanol-induced learning deficits.
BACKGROUND
Drinking during pregnancy has been associated with learning disabilities in affected offspring. At present, there are no clinically effective pharmacotherapeutic interventions for these learning deficits. Here, we examined the effects of ABT-239, a histamine H₃ receptor antagonist, on fetal ethanol-induced fear conditioning and spatial memory deficits.


RESULTS
Long-Evans rat dams stably consumed a mean of 2.82 g ethanol/kg during a 4-hour period each day during pregnancy. This voluntary drinking pattern produced a mean peak serum ethanol level of 84 mg/dl. Maternal weight gain, litter size and birth weights were not different between the ethanol-consuming and control groups. Female adult offspring from the control and fetal alcohol-exposed (FAE) groups received saline or 1 mg ABT-239/kg 30 minutes prior to fear conditioning training. Three days later, freezing time to the context was significantly reduced in saline-treated FAE rats compared to control. Freezing time in ABT-239-treated FAE rats was not different than that in controls. In the spatial navigation study, adult male offspring received a single injection of saline or ABT-239 30 minutes prior to 12 training trials on a fixed platform version of the Morris Water Task. All rats reached the same performance asymptote on Trials 9 to 12 on Day 1. However, 4 days later, first-trial retention of platform location was significantly worse in the saline-treated FAE rats compared control offspring. Retention by ABT-239-treated FAE rats was similar to that by controls. ABT-239's effect on spatial memory retention in FAE rats was dose dependent.


CONCLUSIONS
These results suggest that ABT-239 administered prior to training can improve retention of acquired information by FAE offspring on more challenging versions of hippocampal-sensitive learning tasks. Further, the differential effects of ABT-239 in FAE offspring compared to controls raises questions about the impact of fetal ethanol exposure on histaminergic neurotransmission in affected offspring.
Savage
Daniel D
DD
Department of Neurosciences, MSC08 4740, 1 University of New Mexico, Albuquerque, NM 87131-0001, USA. dsavage@salud.unm.edu
Rosenberg
Martina J
MJ
Wolff
Christina R
CR
Akers
Katherine G
KG
El-Emawy
Ahmed
A
Staples
Miranda C
MC
Varaschin
Rafael K
RK
Wright
Carrie A
CA
Seidel
Jessica L
JL
Caldwell
Kevin K
KK
Hamilton
Derek A
DA
D000818:Animals; D001572:Benzofurans / Q000627:therapeutic use*; D003214:Conditioning, Classical / Q000187:drug effects; D004195:Disease Models, Animal; D000431:Ethanol / Q000009:adverse effects*; D005260:Female; D006633:Histamine Antagonists / Q000494:pharmacology; D007859:Learning Disabilities / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy*; D018697:Nootropic Agents / Q000627:therapeutic use*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000188:drug therapy* / Q000523:psychology; D011759:Pyrrolidines / Q000627:therapeutic use*; D051381:Rats; D020318:Rats, Long-Evans; D018100:Receptors, Histamine H3 / Q000187:drug effects
D001572:Benzofurans; D006633:Histamine Antagonists; D018697:Nootropic Agents; D011759:Pyrrolidines; D018100:Receptors, Histamine H3; D000431:Ethanol; C496397:benzonitrile, 4-(2-(2-((2r)-2-methyl-1-pyrrolidinyl)ethyl)-5-benzofuranyl)-