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

Olfactory preference for ethanol following social interaction with an intoxicated peer in adolescent rats exposed to ethanol in-utero

Background: Prenatal exposure to ethanol and later socially mediated exposure predicts ethanol intake in human adolescents. Animal rat models indicate that brief interactions with an ethanol-intoxicated peer result in heightened preference for ethanol odor and ethanol intake. Methods: This study assessed preference for ethanol odor in adolescent male rats (observers) following social interaction with an ethanol intoxicated peer (demonstrators) as a function of prenatal ethanol exposure (gestational days 17-20, 1.0 g/kg, intragastric). Social behavior and locomotion during social interaction was also measured. Results: Social investigation was greater in observers that interacted with an intoxicated demonstrator in comparison to those that interacted with a sober peer. Social contact increased when the demonstrator was under the effects of ethanol, but only if the observer had experienced ethanol prenatally. Ethanol inhibited locomotion in the demonstrators. Finally, social interaction with an intoxicated peer during adolescence as well as prenatal ethanol experience increased preference for ethanol odor. Conclusions: Fetal exposure to ethanol mediated by maternal intoxication at late gestation or by interaction with an intoxicated peer at adolescence heightens preference for the chemosensory cues of the drug

Preferencia por el olor del etanol tras la interacción social con un congénere intoxicado en ratas adolescentes expuestas a la droga in-útero

Background: Prenatal exposure to ethanol and later socially mediated exposure predicts ethanol intake in human adolescents. Animal rat models indicate that brief interactions with an ethanol-intoxicated peer result in heightened preference for ethanol odor and ethanol intake. Methods: This study assessed preference for ethanol odor in adolescent male rats (observers) following social interaction with an ethanol intoxicated peer (demonstrators) as a function of prenatal ethanol exposure (gestational days 17-20, 1.0 g/kg, intragastric). Social behavior and locomotion during social interaction was also measured. Results: Social investigation was greater in observers that interacted with an intoxicated demonstrator in comparison to those that interacted with a sober peer. Social contact increased when the demonstrator was under the effects of ethanol, but only if the observer had experienced ethanol prenatally. Ethanol inhibited locomotion in the demonstrators. Finally, social interaction with an intoxicated peer during adolescence as well as prenatal ethanol experience increased preference for ethanol odor. Conclusions: Fetal exposure to ethanol mediated by maternal intoxication at late gestation or by interaction with an intoxicated peer at adolescence heightens preference for the chemosensory cues of the drug.Antecedentes: la exposición prenatal al alcohol y la exposición postnatal en contextos sociales predice el consumo de alcohol durante la adolescencia en humanos. Modelos animales indican que la interacción con un congéner intoxicado aumenta la preferencia por el olor del alcohol y su consumo. Método: se analizó la preferencia hacia el olor del etanol en ratas macho adolescentes (observadores) que interactuaron con un compañero intoxicado con alcohol (demostrador), en función de la exposición prenatal al alcohol (días gestacionales 17-20, 1,0 g/kg, intragástrica). Durante la interacción social, se evaluó la conducta social y la locomoción. Resultados: la investigación social fue mayor en los observadores que interactuaron con un sujeto intoxicado en comparación con aquellos que interactuaron con un sujeto sobrio. El contacto social aumentó cuando el demostrador estaba intoxicado, solo si el observador había sido expuesto al alcohol prenatalmente. El alcohol inhibió la locomoción en los demostradores. Finalmente, tanto la interacción social con un congéner intoxicado como la exposición prenatal incrementaron la preferencia por el olor a etanol. Conclusiones: el contacto con etanol durante la vida fetal, así como mediante la exposición a un par intoxicado durante la adolescencia, incrementa la preferencia por las claves quimiosensoriales de la droga.Fil: March, Samanta Mabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto de Investigaciones Médicas Mercedes y Martín Ferreyra; Argentina. Universidad Nacional de Córdoba; ArgentinaFil: Pautassi, Ricardo Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto de Investigaciones Médicas Mercedes y Martín Ferreyra; Argentina. Universidad Nacional de Córdoba; ArgentinaFil: Nizhnikov, Michael. University Of Binghamton; Estados UnidosFil: Fernandez Vidal, Juan Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto de Investigaciones Médicas Mercedes y Martín Ferreyra; ArgentinaFil: Spear, Norman E.. University Of Binghamton; Estados UnidosFil: Molina, Juan Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto de Investigaciones Médicas Mercedes y Martín Ferreyra; Argentina. Universidad Nacional de Córdoba; Argentin

The consequence of fetal ethanol exposure and adolescent odor re-exposure on the response to ethanol odor in adolescent and adult rats

<p>Abstract</p> <p>Background</p> <p>An epidemiologic predictive relationship exists between fetal ethanol exposure and the likelihood for adolescent use. Further, an inverse relationship exists between the age of first experience and the probability of adult abuse. Whether and how the combined effects of prenatal and adolescent ethanol experiences contribute to this progressive pattern remains unknown. Fetal ethanol exposure directly changes the odor attributes of ethanol important for both ethanol odor preference behavior and ethanol flavor perception. These effects persist only to adolescence. Here we tested whether adolescent ethanol odor re-exposure: (Experiment 1) augments the fetal effect on the adolescent behavioral response to ethanol odor; and/or (Experiment 2) perpetuates previously observed adolescent behavioral and neurophysiological responses into adulthood.</p> <p>Methods</p> <p>Pregnant rats received either an ethanol or control liquid diet. Progeny (observers) experienced ethanol odor in adolescence via social interaction with a peer (demonstrators) that received an intragastric infusion of either 1.5 g/kg ethanol or water. Social interactions were scored for the frequency that observers followed their demonstrator. Whole-body plethysmography evaluated the unconditioned behavioral response of observers to ethanol odor in adolescence (P37) or adulthood (P90). The olfactory epithelium of adults was also examined for its neural response to five odorants, including ethanol.</p> <p>Results</p> <p>Experiment 1: Relative to fetal or adolescent exposure alone, adolescent re-exposure enhanced the behavioral response to ethanol odor in P37 animals. Compared to animals with no ethanol experience, rats receiving a single experience (fetal or adolescent) show an enhanced, yet equivalent, ethanol odor response. Fetal ethanol experience also increased olfactory-guided following of an intoxicated peer. Experiment 2: Combined exposure yielded persistence of the behavioral effects only in adult females. We found no evidence for persistence of neurophysiological effects in either sex.</p> <p>Conclusion</p> <p>Fetal ethanol exposure influences adolescent re-exposure, in part, by promoting interactions with intoxicated peers. Re-exposure subsequently enhances ethanol odor responsivity during a key developmental transition point for emergent abuse patterns. While persistence of behavioral effects occurred in females, the level of re-exposure necessary to uniformly yield persistence in both sexes remains unknown. Nonetheless, these results highlight an important relationship between fetal and adolescent experiences that appears essential to the progressive pattern of developing ethanol abuse.</p

Unexpected diversity and complexity of the Guerrero Negro hypersaline microbial mat

Author Posting. © The Author(s), 2006. This is the author's version of the work. It is posted here by permission of American Society for Microbiology for personal use, not for redistribution. The definitive version was published in Applied and Environmental Microbiology 72 (2006): 3685-3695, doi:10.1128/AEM.72.5.3685-3695.2006.We applied nucleic acids-based molecular methods, combined with estimates of biomass (ATP), pigments and microelectrode measurements of chemical gradients, to map microbial diversity vertically on the mm-scale in a hypersaline microbial mat from Guerrero Negro, Baja California Sur, Mexico. To identify the constituents of the mat, small-subunit ribosomal RNA genes were amplified by PCR from community genomic DNA extracted from layers, cloned and sequenced. Bacteria dominated the mat and displayed unexpected and unprecedented diversity. The majority (1336) of 1586 bacterial 16S rRNA sequences generated were unique, representing 752 species (≥97% rRNA sequence identity) in 42 of the main bacterial phyla, including 15 novel candidate phyla. The diversity of the mat samples differentiated according to the chemical milieu defined by concentrations of O2 and H2S. Chloroflexi formed the majority of the biomass by percentage of bulk rRNA and of clones in rRNA gene libraries. This result contradicts the general belief that Cyanobacteria dominate these communities. Although Cyanobacteria constituted a large fraction of the biomass in the upper few mm (>80% of total rRNA and photosynthetic pigments), Chloroflexi sequences were conspicuous throughout the mat. Filamentous Chloroflexi were identified by fluorescent in-situ hybridization within the polysaccharide sheaths of the prominent cyanobacterium Microcoleus chthonoplastes in addition to free-living in the mat. The biological complexity of the mat far exceeds that observed in other polysaccharide-rich microbial ecosystems, such as human and mouse distal guts, and suggests that positive feedbacks exist between chemical complexity and biological diversity.R. Ley was supported in part by an NRC- NASA Astrobiology Institutes Post Doctoral Associateship, J. Spear by an Agouron Institute postdoctoral fellowship. This work was supported by the NASA Cooperative Agreement with the University of Colorado Center for Astrobiology to N. R. Pace

Geographic and ecologic heterogeneity in elimination thresholds for the major vector-borne helminthic disease, lymphatic filariasis

<p>Abstract</p> <p>Background</p> <p>Large-scale intervention programmes to control or eliminate several infectious diseases are currently underway worldwide. However, a major unresolved question remains: what are reasonable stopping points for these programmes? Recent theoretical work has highlighted how the ecological complexity and heterogeneity inherent in the transmission dynamics of macroparasites can result in elimination thresholds that vary between local communities. Here, we examine the empirical evidence for this hypothesis and its implications for the global elimination of the major macroparasitic disease, lymphatic filariasis, by applying a novel Bayesian computer simulation procedure to fit a dynamic model of the transmission of this parasitic disease to field data from nine villages with different ecological and geographical characteristics. Baseline lymphatic filariasis microfilarial age-prevalence data from three geographically distinct endemic regions, across which the major vector populations implicated in parasite transmission also differed, were used to fit and calibrate the relevant vector-specific filariasis transmission models. Ensembles of parasite elimination thresholds, generated using the Bayesian fitting procedure, were then examined in order to evaluate site-specific heterogeneity in the values of these thresholds and investigate the ecological factors that may underlie such variability</p> <p>Results</p> <p>We show that parameters of density-dependent functions relating to immunity, parasite establishment, as well as parasite aggregation, varied significantly between the nine different settings, contributing to locally varying filarial elimination thresholds. Parasite elimination thresholds predicted for the settings in which the mosquito vector is anopheline were, however, found to be higher than those in which the mosquito is culicine, substantiating our previous theoretical findings. The results also indicate that the probability that the parasite will be eliminated following six rounds of Mass Drug Administration with diethylcarbamazine and albendazole decreases markedly but non-linearly as the annual biting rate and parasite reproduction number increases.</p> <p>Conclusions</p> <p>This paper shows that specific ecological conditions in a community can lead to significant local differences in population dynamics and, consequently, elimination threshold estimates for lymphatic filariasis. These findings, and the difficulty of measuring the key local parameters (infection aggregation and acquired immunity) governing differences in transmission thresholds between communities, mean that it is necessary for us to rethink the utility of the current anticipatory approaches for achieving the elimination of filariasis both locally and globally.</p

Participation of the endogenous opioid system in the acquisition of a prenatal ethanol-related memory: Effects on neonatal and preweanling responsiveness to ethanol

The present study tested the involvement of the opioid system in the acquisition and expression of prenatal ethanol-related memories. We evaluated how this prenatal experience modulates ethanol self-administration in newborn rats, and preweanling's ingestion of the drug.During Gestational Days (GDs) 17-20, four groups of dams were treated with ethanol (2. g/kg) or water, followed immediately by naloxone (10. mg/kg) or saline administration. A fifth group received a similar dose of naloxone 20. min before ethanol administration. On PD 1, pups were tested on an operant learning procedure to obtain milk or 3% ethanol. One hour later, an extinction session was performed. At Postnatal Days (PDs) 14 and 15, preweanlings representing each prenatal treatment were evaluated in an intake test with infusions of 5% ethanol or water. Prior to the intake test on PD14, preweanlings were administered naloxone (1. mg/kg), saline or remained untreated. In both tests, animals representative of both genders were utilized.One-day-old pups rapidly learned the operant behavior to gain access to milk. In contrast, only pups prenatally treated with ethanol (administered immediately before naloxone or saline injection) increased operant responding to gain access to ethanol. On an intake test at PDs 14 and 15, those animals prenatally exposed to naloxone 20. min before ethanol administration consumed significantly lower ethanol levels than the remaining prenatal ethanol groups. Postnatal treatment with naloxone diminished intake of all solutions at PD14.These results suggest that prenatal ethanol exposure facilitates neonatal operant learning reinforced by intraoral administration of ethanol and increases ethanol consumption during PDs 14-15. The endogenous opioid system apparently is involved in the acquisition of prenatal ethanol memories, which can modulate the reinforcing attributes of the drug in neonatal and preweanling rats.Fil: Miranda Morales, Roberto Sebastián. 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. Universidad Nacional de Córdoba. Facultad de Psicología; Argentina. University of Binghamton; Estados Unidos. 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: Spear, Norman E.. University of Binghamton; Estados UnidosFil: Abate, Paula. 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; Argentin

Dealing with heterogeneity of treatment effects: is the literature up to the challenge?

<p>Abstract</p> <p>Background</p> <p>Some patients will experience more or less benefit from treatment than the averages reported from clinical trials; such variation in therapeutic outcome is termed heterogeneity of treatment effects (HTE). Identifying HTE is necessary to individualize treatment. The degree to which heterogeneity is sought and analyzed correctly in the general medical literature is unknown. We undertook this literature sample to track the use of HTE analyses over time, examine the appropriateness of the statistical methods used, and explore the predictors of such analyses.</p> <p>Methods</p> <p>Articles were selected through a probability sample of randomized controlled trials (RCTs) published in <it>Annals of Internal Medicine</it>, <it>BMJ</it>, <it>JAMA</it>, <it>The Lancet</it>, and <it>NEJM </it>during odd numbered months of 1994, 1999, and 2004. RCTs were independently reviewed and coded by two abstractors, with adjudication by a third. Studies were classified as reporting: (1) HTE analysis, utilizing a formal test for heterogeneity or treatment-by-covariate interaction, (2) subgroup analysis only, involving no formal test for heterogeneity or interaction; or (3) neither. Chi-square tests and multiple logistic regression were used to identify variables associated with HTE reporting.</p> <p>Results</p> <p>319 studies were included. Ninety-two (29%) reported HTE analysis; another 88 (28%) reported subgroup analysis only, without examining HTE formally. Major covariates examined included individual risk factors associated with prognosis, responsiveness to treatment, or vulnerability to adverse effects of treatment (56%); gender (30%); age (29%); study site or center (29%); and race/ethnicity (7%). Journal of publication and sample size were significant independent predictors of HTE analysis (p < 0.05 and p < 0.001, respectively).</p> <p>Conclusion</p> <p>HTE is frequently ignored or incorrectly analyzed. An iterative process of exploratory analysis followed by confirmatory HTE analysis will generate the data needed to facilitate an individualized approach to evidence-based medicine.</p