Fetal Learning About Ethanol and Later Ethanol Responsiveness: Evidence Against “Safe” Amounts of Prenatal Exposure

Abstract

Near-term fetuses of different mammalian species, including humans, exhibit functional sensory and learning capabilities. The neurobiological literature indicates that the unborn organism processes sensory stimuli present in the amniotic fluid, retains this information for considerable amounts of time, and is also capable of associating such stimuli with biologically relevant events. This research has stimulated studies aimed at the analysis of fetal and neonatal learning about ethanol, a topic that constitutes the core of the present review. Ethanol has characteristic sensory (olfactory, taste, and trigeminal) attributes and can exert pharmacologic reinforcing effects. The studies under examination support the hypothesis that low to moderate levels of maternal ethanol intoxication during late pregnancy set the opportunity for fetal learning about ethanol. These levels of prenatal ethanol exposure do not generate evident morphologic or neurobehavioral alterations in the offspring, but they exert a significant impact upon later ethanol-seeking and intake behaviors. Supported by preclinical and clinical findings, this review contributes to strengthening the case for the ability of prenatal ethanol exposure to have effects on the postnatal organism. Keywords ethanol; fetal learning; associative conditioningThis review analyzes the impact of low to moderate prenatal levels of exposure to ethanol on later responding to ethanol and stimuli associated with ethanol. These levels of ethanol exposure might be viewed as "safe" but nevertheless have negative effects that might not be noticed for many years.We previously reviewed the literature, examining possible associations between early ontogenetic experiences with alcohol and subsequent affinity for ethanol ingestion and sensitivity to its reinforcing effects (postabsorptive consequences that increase behaviors aimed at obtaining ethanol or that generate preferences to stimuli signaling such consequences) (1). This review took into account fetal and infantile experiences involving acute or chronic exposure to ethanol and how they exerted significant effects upon subsequent ethanol 1To whom correspondence should be addressed at Instituto Ferreyra,

The effect of taste familiarity on intake and taste reactivity in infant rats

“…However, since in that study the familiarization procedure involved the ingestion of relatively large amounts of ethanol, sufficient to induce pharmacological effects, it may be concluded that the reported effect was the consequence of an appetitive association between ethanol's flavor and its reinforcing properties, rather than solely an effect of familiarization. Likewise, when comparing the present results with those of studies involving prenatal ethanol exposure in which increased intake, enhanced palatability and even odor preference were observed (Abate et al, 2008;Chotro et al, 2007Chotro et al, , 2009Spear & Molina, 2005;Youngentob & Glendinning, 2009), it remains clear that in all those studies the experience with ethanol necessarily involved a reinforcer in addition to ethanol's flavor.…”

“…In another study with rat fetuses, no differential responsiveness to a mint flavor was found after analyzing eleven behavioral categories of the fetal response as a function of familiarity (Smotherman & Robinson, 1985). With the flavor of ethanol, which is a complex stimulus with gustatory, olfactory and irritant components, it has been found that prenatal exposure induces increased intake and/or enhanced palatability of ethanol in infant and older rats (Abate, Pueta, Spear, & Molina, 2008;Chotro, Arias, & Laviola, 2007;Youngentob & Glendinning, 2009) (Chotro, Arias, & Spear, 2009). Although in most of this research exposure to ethanol also involved the presence of reinforcing consequences, it should be pointed out that when the contiguity of ethanol's flavor with reinforcement was explicitly avoided, no changes were observed either in ethanol consumption (Arias & Chotro, 2006;Chotro & Alonso, 2003;Chotro & Arias, 2003;Chotro et al, 2009) or in reactivity to its flavor (Arias & Chotro, 2005;Dominguez, Chotro, & Molina, 1993;Molina & Chotro, 1991).…”

Alcohol odor elicits appetitive facial expressions in human neonates prenatally exposed to the drug

“…Bonferroni post-hoc tests showed that babies born to frequent drinkers and primarily stimulated with ethanol had , suckling and smiling). Lower panels depict frequency of each specific behavior across testing trials (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11), olfactory sequence (EtOH-Lem-EtoH or Lem-EtOH-Lem) and maternal drinking habits (infrequent or frequent). Appropriate MANOVAs indicated that in the case of tongue protrusion, babies frequently exposed to ethanol during gestation and tested primarily with ethanol odor (EtOH-Lem-EtOH) exhibited significantly higher levels of this facial expression when compared to newborns delivered by infrequent drinkers.…”

“…Furthermore, during developmental stages analogous to the second and third gestational trimester in humans, rats acquire appetitive associative memories comprising salient olfactory stimuli and ethanol's or acetaldehyde's reinforcing effects [11,20,21]. Hence, early familiarity with ethanol's sensory cues or the association of these stimuli with the drug's reinforcing effects has been proposed as two congenital mechanisms that determine or modulate subsequent ethanol preference or drinking patterns [8][9][10][11].…”

“…Animal research has also emphasized that prenatal exposure to the drug represents a critical factor when considering subsequent ethanol affinity as operationalized through exacerbated drinking, active behavior in search of the drug coupled with heightened sensitivity to its reinforcing effects as well as those centrally exerted by its main metabolite (acetaldehyde) [8][9][10][11]. These phenomena have also been reported in human epidemiological studies even when controlling for other variables known to affect ethanol use and abuse (e.g., genetic predisposition as assessed through family history of alcoholism, gender, co-use of other drugs during pregnancy and different environmental factors) [12][13][14][15][16].…”