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

Sensitization to ethanol’s disruptive effects upon early breathing plasticity associated with hypoxia and hypercapnia

Ethanol (EtOH) consumption during pregnancy and lactation represents a risk factor related with the Sudden Infant Death Syndrome (SIDS). This phenomenon has promoted research linking prenatal EtOH effects on the respiratory system during early ontogeny. It should also be noted that prolonged episodes of neonatal respiratory depression represent a risk factor in terms of hypoxic-ischemic effects with negative consequences on brain development. In a first study during postnatal day (PD) 9 we analyzed the impact of different doses of EtOH (0.0, 0.75, 1.37 or 2.0 g/kg) upon the respiratory response and the potential psychomotor effects in pup rats pre-exposed or not to 2.0 g/kg of EtOH during PDs 3-7. At PD 9 animals were also subjected to sequential air conditions defined as initial normoxia, hypoxia and recovery normoxia. In a second study we analyzed the blood of animals only exposed to 0.0 or 2.0g/kg of EtOH during PDs 3-9 (not subjected to a hypoxic event). The aim was to examine if mere intoxication with a moderate dose of EtOH is capable of modifying blood metabolic patterns associated with hypoxia or hypercapnia. In the first study during PDs 3-7 EtOH exerted a depressant effect upon breathing frequencies. These animals also showed a progressive sensitization effect relative to the depressant effects of the drug and lesser levels of apneas. At PD 9 dose dependent respiratory depressions were observed when pups were challenged with a hypoxic event. Independently from prior experience with EtOH, drug treatment at PD 9 significantly disrupted respiratory frequencies particularly during the hypoxic and the recovery normoxia phases. Respiratory disorders triggered by these air conditions have been implicated in the pathophysiology of SIDS. These results show that breathing plasticity is disrupted during a critical stage where respiratory alterations may lead to hypoxiaassociated syndromes that endanger brain development. In terms of psychomotor activity, animals exposed to 2.0 g/kg of EtOH at PD 9 showed heightened duration and frequency of grooming. In the second study animals exposed at least one time to EtOH exhibited lower pH and higher CO2 than animals that were never exposed to EtOH. This results suggest metabolic acidosis probably due to EtOH-related hypercapnia during a vulnerable stage in development relative to SIDS.Fil: Anunziata, Florencia. 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; ArgentinaFil: Macchione, Ana Fabiola. 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 Nacional de Córdoba. Instituto de Investigaciones Psicológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Psicológicas; ArgentinaFil: Angulo Alcalde, Asier. 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; ArgentinaFil: Trujillo, María Verónica. 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; ArgentinaFil: Wille-bille, Aranza. 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; ArgentinaFil: Amigone, José Luis. Hospital Privado de Córdoba. Laboratorio de Bioquímica Clínica; ArgentinaFil: Molina, Juan Carlos. Universidad Nacional de Córdoba. Facultad de Psicología; Argentina. 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; ArgentinaIX LASBRA International Meeting: Determinants of Alcoholism: bridging the gap between epidemiologic and basic researchCórdobaArgentinaLatin American Society for Biomedical Research on Alcoholis

Exposición prenatal al alcohol: análisis del rol de sus propiedades quimiosensoriales e incondicionales en el aprendizaje pre y postnatal en la rata.

224 p.Los fetos de rata son capaces de percibir olores y sabores derivados de la dieta materna, aprender sobre ellos y retener esta memoria hasta la vida postnatal, expresando cambios en la respuesta ante dichos estímulos. Cuando la madre gestante ingiere alcohol, éste llega al feto, el cual es expuesto tanto a sus propiedades quimiosensoriales (olor/sabor), como a sus propiedades farmacológicas. Los fetos pueden asociar ambas características del alcohol y aprender una preferencia condicionada por su sabor y olor; lo que genera una mayor atracción por su olor en la etapa neonatal, y en la infancia y adolescencia un mayor consumo de alcohol y un aumento de la palatabilidad. Se ha demostrado que las propiedades incondicionales del alcohol son en realidad mediadas por su primer metabolito, el acetaldehído. El objetivo general de esta tesis es el de analizar en profundidad las consecuencias de la experiencia prenatal con las propiedades quimiosensoriales y farmacológicas (incondicionales) del alcohol, tanto juntascomo por separado, sobre la respuesta postnatal al sabor y olor etílicos, a sus propiedades incondicionales, o a otros estímulos quimiosensoriales experimentados de forma conjunta con esta droga. Los resultados mostraron que los neonatos de rata puede

Ethanol's disruptive effects upon early breathing plasticity and blood parameters associated with hypoxia and hypercapnia

Early ethanol exposure affects respiratory neuroplasticity; a risk factor associated with the Sudden Infant Death Syndrome. High and chronic ethanol doses exert long-lasting effects upon respiratory rates, apneic episodes and ventilatory processes triggered by hypoxia. The present study was performed in 3–9-day-old rat pups. Respiratory processes under normoxic and hypoxic conditions were analyzed in pups intoxicated with different ethanol doses which were pre-exposed or not to the drug. A second major goal was to examine if acute and/or chronic early ethanol exposure affects blood parameters related with hypercapnic or hypoxic states. In Experiment 1, at postnatal day 9, animals previously treated with ethanol (2.0 g/kg) or vehicle (0.0 g/kg) were tested sober or intoxicated with 0.75, 1.37 or 2.00 g/kg ethanol. The test involved sequential air conditions defined as initial normoxia, hypoxia and recovery normoxia. Motor activity was also evaluated. In Experiment 2, blood parameters indicative of possible hypoxic and hypercapnic states were assessed as a function of early chronic or acute experiences with the drug. The main results of Experiment 1 were as follows: i) ethanol's depressant effects upon respiratory rates increased as a function of sequential treatment with the drug (sensitization); ii) ethanol inhibited apneic episodes even when employing the lowest dose at test (0.75 g/kg); iii) the hyperventilatory response caused by hypoxia negatively correlated with the ethanol dose administered at test; iv) ventilatory long-term facilitation (LTF) during recovery normoxia was observed in pups pre-exposed to the drug and in pups that received the different ethanol doses at test; v) self-grooming increased in pups treated with either 1.37 or 2.00 g/kg ethanol. The main result of Experiment 2 indicated that acute as well as chronic ethanol exposure results in acidosis-hypercapnia. The results indicate that early and brief experiences with ethanol are sufficient to affect different respiratory plasticity processes as well as blood biomarkers indicative of acidosis-hypercapnia. An association between the LTF process and the acidosis-hypercapnic state caused by ethanol seems to exist. The mentioned experiences with the drug are sufficient to result in an anomalous programming of respiratory patterns and metabolic conditions.Fil: Anunziata, Florencia. 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; ArgentinaFil: Macchione, Ana Fabiola. Universidad Nacional de Córdoba. Instituto de Investigaciones Psicológicas. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Psicológicas; Argentina. Universidad Nacional de Córdoba. Facultad de Psicología; Argentina. Hospital Privado de Córdoba; ArgentinaFil: Alcalde, Asier Angulo. 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: Tejerina, David. Universidad Nacional de Córdoba. Facultad de Psicología; Argentina. Hospital Privado de Córdoba; ArgentinaFil: Amigone, Jorge Luis. 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. Hospital Privado de Córdoba; ArgentinaFil: Wille-bille, Aranza. 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; ArgentinaFil: Trujillo, Verónica. 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; ArgentinaFil: Molina, Juan 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 Nacional de Córdoba. Facultad de Psicología; Argentin