Does moderate drinking harm the fetal brain? Insights from animal models

Abstract

Although public health campaigns advise pregnant women to abstain from ethanol, drinking during pregnancy is pervasive. Here, we highlight recent studies that have clearly demonstrated long-lasting neurobehavioral deficits in the offspring of laboratory animals exposed to moderate levels of ethanol during development. Alterations in learning, memory, motor coordination, social behavior, and stress responses were identified in these animals. Increased vulnerability to substance abuse was also demonstrated. These behavioral alterations have been associated with impairments in neurotransmitter systems, neuromodulators, and/or synaptic plasticity in several brain regions. With this review we hope to contribute to a better appreciation of the potential effects of developmental exposure to moderate ethanol levels, leading to better interventions aimed at relieving fetal alcohol spectrum disorders.

Fig 1. Schematic representation of ethanol exposure paradigms used in the studies reviewed here

To model 1^st and 2^nd trimester ethanol exposure, pregnant rodents were exposed to moderate doses of ethanol using: A) forced (i.e., ethanol containing solutions were the only source of water and/or food [25, 46, 58]) and continuous or limited voluntary drinking paradigms [26, 29, 30]. Voluntary drinking has also been used to expose monkeys to ethanol at different stages of pregnancy [62]. B) To model human exposure during the 3^rd trimester, rat pups and dams were exposed via ethanol vapor inhalation chambers [35, 55] or C) pups via intraperitoneal or subcutaneous ethanol injections [48, 64].

Fig 2. Prenatal exposure to moderate ethanol levels impairs hippocampal-dependent memory and plasticity

A) Left panel: schematic representation of the Morris Water Task, which measures training-induced changes in the time to find a hidden platform (escape latency) in a tub full of opaque water. Animals typically use environmental cues to locate the platform. MPAE animals typically need longer time to find the escape platform. Right panel: escape latency was significantly increased in MPAE adult rat offspring (voluntary drinking paradigm during pregnancy; 5% ethanol (v/v) plus 0.066% saccharin (v/v) in water) and this effect was reversed by the H3 receptor antagonist, ABT-239 [26]. B) Left panel: schematic representation of the contextual fear conditioning test, which measures immobility (i.e., freezing) time in rodents re-exposed to the environmental context where they received a foot shock. MPAE animals typically freeze less (i.e., fail to link the context with the shock received previously) than control animals. Right panel: freezing in a contextual fear conditioning test was reduced in MPAE adult offspring and this effect was reversed by ABT-239 [26]. C) Left panel: shown in the top panel is a schematic representation of a coronal section of the hippocampal formation showing the CA1 and CA3 hippocampal subfields, as well as the dentate gyrus (DG). A granule cell (GC) in the DG is shown in green. GCs receive glutamatergic input from the enthorhinal cortex via the perforant path (PP). The lower panel illustrates a PP-GC synapse, including presynaptic H3 receptors and postsynaptic NMDA and AMPA receptors. Prenatal ethanol exposure may result in a long-lasting increase in the activity of H3 receptors, decreasing glutamate release and synaptic plasticity. Right panel: LTP recorded in the DG from urethane anesthetized rats was impaired in MPAE adult offspring (gray circles) with respect to saccharin control group offspring (red circles) and this effect was reversed by the H3 receptor blocker ABT-239 (white circles). The graph shows the change in field excitatory postsynaptic potential (fEPSP) amplitude over a 1hr period. Reprinted with permission from [26] (Panels A, B; © Wiley-Blackwell) and [27] (Panel C; © American Society for Pharmacology and Experimental Therapeutics).

Fig 3. Schematic representation of the rodent brain indicating examples of the effect of moderate ethanol exposure in different brain regions

*For comparison, the results of studies with primates are also mentioned in italics. Abbreviations: DA, dopamine; GC, granule cells; HPA, hypothalamic-pituitary-adrenal axis; RA, all-trans retinoic acid; SN, substantia nigra; T3, triiodothyronine; VTA, ventral tegmental area.