Prenatal Alcohol Exposure as a Case of Involuntary Early Onset of Alcohol Use: Consequences and Proposed Mechanisms From Animal Studies

Prenatal alcohol exposure has been found to be an important factor determining later consumption of this drug. In humans, despite the considerable diversity of variables that might influence alcohol consumption, longitudinal studies show that maternal alcohol intake during gestation is one of the best predictors of later alcohol use from adolescence to young adulthood. Experimental studies with animals also provide abundant evidence of the effects of prenatal alcohol exposure on later alcohol intake. In addition to increased consumption, other effects include enhanced palatability and attractiveness of alcohol flavor as well as sensitization to its sensory and reinforcing effects. Most of these outcomes have been obtained after exposing rats to binge-like administrations of moderate alcohol doses during the last gestational period when the fetus is already capable of detecting flavors in the amniotic fluid and learning associations with aversive or appetitive consequences. On this basis, it has been proposed that one of the mechanisms underlying the increased acceptance of alcohol after its prenatal exposure is the acquisition (by the fetus) of appetitive learning via an association between the sensory properties of alcohol and its reinforcing pharmacological effects. It also appears that this prenatal appetitive learning is mediated by the activation of the opioid system, with fetal brain acetaldehyde playing an important role, possibly as the main chemical responsible for its activation. Here, we review and analyze together the results of all animal studies testing these hypotheses through experimental manipulation of the behavioral and neurochemical elements of the assumed prenatal association. Understanding the mechanisms by which prenatal alcohol exposure favors the early initiation of alcohol consumption, along with its role in the causal pathway to alcohol disorders, may allow us to find strategies to mitigate the behavioral effects of this early experience with the drug. We propose that prenatal alcohol exposure is regarded as a case of involuntary early onset of alcohol use when designing prevention policies. This is particularly important, given the notion that the sooner alcohol intake begins, the greater the possibility of a continued history of alcohol consumption that may lead to the development of alcohol use disorders.The research has been funded by the Basque Government (IT1341-19) to the research group (PI: Gabriel Rodriguez San Juan)

The role of acetaldehyde in the increased acceptance of ethanol after prenatal ethanol exposure

Recent studies show that acetaldehyde, the first metabolite in the oxidation of ethanol, can be responsible for both, the appetitive and the aversive effects produced by ethanol intoxication. More specifically, it has been hypothesized that acetaldehyde produced in the periphery by the liver is responsible for the aversive effects of ethanol, while the appetitive effects relate to the acetaldehyde produced centrally through the catalase system. On the other hand, from studies in our and other laboratories, it is known that ethanol exposure during the last gestational days (GD) consistently enhances the postnatal acceptance of ethanol when measured during early ontogeny in the rat. This increased liking of ethanol is a conditioned appetitive response acquired by the fetus by the association of ethanol’s flavor and an appetitive reinforcer. Although this reinforcer has not yet been fully identified, one possibility points to acetaldehyde produced centrally in the fetus as a likely candidate. This hypothesis is supported by data showing that very early in the rat’s ontogeny brain catalases are functional, while the liver’s enzymatic system is still immature. In this study, rat dams were administered on GD 17–20 with water or ethanol, together with an acetaldehyde-sequestering agent (D-penicillamine). The offspring’s responses to ethanol was then assessed at different postnatal stages with procedures adequate for each developmental stage: on day 1, using the “odor crawling locomotion test” to measure ethanol’s odor attractiveness; on day 5, in an operant conditioning procedure with ethanol as the reinforcer; and on day 14 in an ethanol intake test. Results show that the absence of acetaldehyde during prenatal ethanol exposure impeded the observation of the increased acceptance of ethanol at any age. This seems to confirm the crucial role of acetaldehyde as a reinforcer in the appetitive learning occurring during prenatal ethanol exposure

Small for gestational age moderate to late preterm children: a neuropsychological follow-up

[EN] Determine whether SGA constitutes a neurodevelopmental risk-factor of MLP, exploring if potential developmental difficulties at toddlerhood persist and are related to school-age performance. 109 SGA and 109 adequate for gestational age MLP children were evaluated at 2 and at 6.5 y.o. SGA children obtained poorer results in several areas at both timepoints; and their development at toddlerhood strongly correlated with only some results at school-age. SGA confers vulnerability to MLP, evolving from global/unspecific difficulties in toddlerhood to a domain-specific profile (attentional/dysexecutive) at 6.5. Findings claim the need for neuropsychological follow-up in MLP to identify emerging difficulties

MC4-R signaling within the nucleus accumbens shell, but not the lateral hypothalamus, modulates ethanol palatability in rats

The Melanocortin (MC) system is one of the crucial neuropeptidergic systems that modulate energy balance. The roles of endogenous MC and MC-4 receptor (MC4-R) signaling within the hypothalamus in the control of homeostatic aspects of feeding are well established. Additional evidence points to a key role for the central MC system in ethanol consumption. Recently, we have shown that nucleus accumbens (NAc), but not lateral hypothalamic (LH), infusion of a selective MC4-R agonist decreases ethanol consumption. Given that MC signaling might contribute to non-homeostatic aspects of feeding within limbic circuits, we assessed here whether MC4-R signaling within the NAc and the lateral hypothalamus (LH) alters normal ingestive hedonic and/or aversive responses to ethanol in rats as measured by a taste reactivity test. Adult male Sprague-Dawley rats were given NAc- or LH- bilateral infusion of the selective MC4-R agonist cyclo (NH-CH2-CH2-CO-His-D-Phe-Arg-Trp-Glu)-NH2 (0, 0.75 or 1.5 µg/0.5µl/site) and following 30 min, the animals received 1 ml of ethanol solution (6% w/v) intraoral for 1 minute and aversive and hedonic behaviors were recorded. We found that NAc-, but not LH-administration, of a selective MC4-R agonist decreased total duration of hedonic reactions and significantly increased aversive reactions relative to saline-infused animals which support the hypothesis that MC signaling within the NAc may contribute to ethanol consumption by modulating non-homeostatic aspects (palatability) of intake

Prenatal appetitive learning about ethanol in the rat: possible reinforcers.

185 p.Los fetos de rata perciben estímulos quimio-sensoriales provenientes de la dieta materna y aprenden sobre ellos. Estudios previos de nuestro laboratorio han demostrado que la exposición prenatal al etanol durante los últimos días de la gestación aumenta la aceptación del sabor del etanol, tanto en ratas infantes como en adolescentes. Sin embargo, con la exposición prenatal a sabores no-etílicos no sé encontró este efecto a esas edades Este aumento en la aceptación del etanol se ha demostrado que es una respuesta condicionada adquirida prenatalmente y que está mediada por el sistema opioide. El objetivo general de esta tesis es investigar la identidad del reforzador que puede estar actuando durante la exposición prenatal al etanol y por el cual el feto de rata adquiere una respuesta apetitiva hacia el sabor del etanol Dos posibles reforzadores que activan el sistema opioide fueron considerados: el líquido amniótico (y su componente KIF) y los efectos farmacológicos del etanol. Además, también investigamos el rol que juega el primer metabolito del etanol, el acetaldehído, en la respuesta apetitiva adquirida después de la exposición prenatal a esta sustancia. Los resultados de todos los experimentos indican que la experiencia prenatal con sustancias no-etílicas y sin efectos farmacológicos produce un incremento en la atracción por las mismas cuando se evalúan en la etapa neonatal. Esto podría ser una evidencia de que el componente KIF del líquido amniótico funciona como reforzador para la respuesta apetitiva adquirida en utero. Sin embargo, este parece ser un reforzador débil ya que el aprendizaje prenatal no es retenido durante un periodo largo de tiempo, aun utilizando técnicas de evaluación apropiadas para esa etapa del desarrollo. También se concluye que la activación del sistema de receptores opioides mu es crítico, no solo para el aprendizaje apetitivo prenatal sobre el etanol, sino también sobre sustancias no-etílicas. En cambio, el sistema opioide kappa parece estar mediando solamente la respuesta aprendida sobre el etanol. Por último, los resultados sugieren que el acetaldehído, más que el etanol, parece ser el principal reforzador del aprendizaje prenatal apetitivo sobre el sabor del etanol

Conditioned inhibition in preweanling rats

Inhibitory conditioning is a very well established phenomenon in associative learning that has been demonstrated in both humans and adult animals. But in spite of the fact that this topic has generated much empirical and theoretical work, there are no published studies assessing inhibitory learning during the early ontogeny of the rat. In this study we test the possibility of finding conditioned inhibition in infant rats (Day 10) using a conditioned taste aversion procedure. We tested whether the consumption of saccharin (A) was reduced when paired with a LiCl injection compared to the presentation of saccharin in compound with a lemon odor (AX) without any aversive consequence. After training, retardation, and summation tests were conducted in order to evaluate the inhibitory properties of the lemon odor (X). The results of this study showed that in male pups, after conditioned inhibition training, stimulus X passed both retardation and summation tests. These results indicate that conditioned inhibition can be established in the early development of the rat, suggesting that animals at this stage of ontogeny have the capacity to acquire and to express inhibitory conditioning, although this effect appears to be sex-dependent.Fil: Aranda-Fernandez, Patricio E.. Universidad del País Vasco; EspañaFil: Gaztañaga, Mirari. Universidad del País Vasco; EspañaFil: Arias Grandio, Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; Argentina. Universidad del País Vasco; EspañaFil: Chotro, M. Gabriela. Universidad del País Vasco; Españ