Effects of a Novel Cognition‐Enhancing Agent on Fetal Ethanol‐Induced Learning Deficits

Abstract

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. Methods and 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.

Effects of the Cognition-Enhancing Agent ABT-239 on Fetal Ethanol-Induced Deficits in Dentate Gyrus Synaptic Plasticity

“…3, C and D). Thus, the effects of prenatal ethanol exposure on synaptic potentiation are subtle, reminiscent of the subtle learning deficits we have observed in littermates of the offspring used in this study (Savage et al, 2010). The effect of prenatal ethanol exposure on LTP using the 3-tetanus train protocol (Fig.…”

“…The pharmacologic rationale for selecting ABT-239 was based on prior observations, suggesting that prenatal ethanol exposure diminished activity-dependent potentiation of glutamate release in hippocampal slices (Savage et al, 1998). The 1 mg of ABT-239/kg dose was selected for our study based on prior observations that it was an optimal test dose for increasing acetylcholine release in vivo and enhancing performance in a variety of behavioral paradigms , including the reversal of fetal ethanol-induced deficits in contextual fear conditioning and spatial navigation (Savage et al, 2010). Given that histamine H 3 receptor agonists inhibit glutamate release (Brown and Reymann, 1996), we predicted that the histamine H 3 receptor antagonist ABT-239 would attenuate fetal ethanol-induced LTP deficits in the dentate gyrus.…”

“…The ability of H 3 receptor antagonists to facilitate acetylcholine, dopamine, and glutamate release has generated considerable interest in their therapeutic potential for a variety of neurologic and psychiatric disorders, particularly diseases with attendant neurocognitive deficits. Indeed, H 3 receptor antagonists enhance behavioral performance in a variety of rodent learning paradigms (Fox et al, 2003Foley et al, 2009) and reversed contextual fear conditioning and spatial navigation deficits in fetal ethanol-exposed Long-Evans rats (Savage et al, 2010).…”

“…The voluntary drinking paradigm was selected because it has the dual advantage of not requiring multiple diet control groups to control for paired feeding of a liquid diet as well as for allaying concern that the consumption of liquid diets may be stressful (Rasmussen et al, 2000), a potential confounder in fetal alcohol exposure studies. The second study objective was to determine whether the cognitionenhancing agent 4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile (ABT-239), a nonimidazole antagonist of H 3 histamine receptors Miller et al, 2008) that reverses learning deficits in a variety of models including our current fetal ethanol exposure paradigm (Savage et al, 2010), would also reverse fetal ethanol-induced deficits in dentate gyrus LTP. The pharmacologic rationale for selecting ABT-239 was based on prior observations, suggesting that prenatal ethanol exposure diminished activity-dependent potentiation of glutamate release in hippocampal slices (Savage et al, 1998).…”

The Effects of Stress on Measures of Alcohol Drinking in Rodents

“…Decreases in the serotonergic cells in the midbrain raphe nuclei have also been observed in anxious, prenatally exposed rats (Ohta et al, 2012). Prenatal ethanol exposure was also found to decrease contextual fear conditioning in adult Long Evans rats, although this may be due to a more general deficit in hippocampal-dependent learning (Savage et al, 2010) rather than long-term effects on functioning of stress systems.…”