Behavioral characterization of acetaldehyde in C57BL/6J mice: Anxiolytic, amnesic and hedonic effects

It has been postulated that a number of central effects of ethanol are mediated through the action of its first metabolite, acetaldehyde. In particular, acetaldehyde might be involved in the anxiolytic and hedonic effects of ethanol and is therefore believed to play an important role in alcohol abuse. In agreement with this assumption, previous studies indicated that acetaldehyde is mainly reinforcing in rats, which have been shown to readily self-administer acetaldehyde both peripherally and centrally. However, the hedonic effects of acetaldehyde have never been tested in mice, and the possible amnesic and anxiolytic effects of acetaldehyde remain to be elucidated. Therefore, the present studies were aimed at characterizing the anxiolytic, hedonic and amnesic effects of acetaldehyde after its acute peripheral administration to C57BL/6J mice. The effects of intraperitoneal acetaldehyde (0-300 mg/kg) injections were assessed in several classical behavioral tests. The anxiolytic effects were tested with the elevated plus maze, the hedonic effects with the place conditioning procedure and the amnesic effects with the passive avoidance apparatus. Our results show that acetaldehyde dose-dependently altered memory consolidation as evidenced by a reduced performance in the passive avoidance test when acetaldehyde was injected immediately after training at doses between 100 and 300 mg/kg. The elevated plus-maze showed that acetaldehyde, in contrast to ethanol, does not possess anxiolytic properties. Finally, the results of the place conditioning experiment confirmed that acetaldehyde displays significant hedonic properties. The present results add further support to the role of acetaldehyde in ethanol amnesic and hedonic effects but interestingly suggest that acetaldehyde is not involved in ethanol anxiolytic effects

Study Protocol: Effect of prenatal wheel-running exercise (before and during gestation) on cocaine psychomotor sensitization expressed in the offspring in periadolescent females and males C57BL/6J mice

The present study principally aims at determining to which extent prenatal exercise (before and during gestation) could affect the initiation (establishment) and the expression of psychomotor sensitization induced by a representative dose of cocaine in young female and male mice. More specifically, we will assess cocaine-induced acute psychomotor-activating effects, psychomotor sensitization developing over 9 daily sessions (daily peritoneal injections of cocaine or saline) and the long-term expression of the sensitized response (30 days after the last sensitizing injection) in C57BL/6J mice born from mothers housed with or without a running wheel before and during gestation. Based on literature and on our prior results, the mice born from exercised mothers are expected to show significantly reduced levels of cocaine responsiveness in comparison with the control mice (born from unexercised mothers)

Power and True Report Probability in the Literature on Mice Nicotine Conditioned Place Preference

A lack of prospective power and use of effect sizes in the literature of various fields have been revealed and characterized over the years, giving rise to serious doubts on the reproducibility of many scientific results (Button & al. 2013, Nat.Rev.Neurosci. 14:365-376; Cohen 1962, Abnorm.Psychol. 65:145-153). To our knowledge, no study has address this problem in the field of experimental psychopharmacology using animal models. The articles were identified in PubMed. The sample size, the type of statistical test, its result, degrees of freedom and pvalue were recorded. We then computed the individual and the median prospective powers for 6 possible effect sizes (Cohen’s d: 0.01, 0.2, 0.5, 0.8, 1.2, 2). The TRP was computed from the median power, type-I error rate and the plausibility (prior probability). Amongst 139 articles, only 47 met our inclusion criteria for 109 statistical tests. In this sample, 77.57% of tests were significant. The median powers for small (0.2), medium (0.5) and large (0.8) effect sizes in F test were 9.56% [IQR 7.96%-11.5%], 34.45% [IQR 24.61%-47.01%] and 70.46% [IQR 52.92%-85.91%]. None of these numbers reached the recommended minimal prospective power of 80%. A 50% hypothetical plausibility yielded TRPs of 48.9%, 77.5%, and 87.6% for small, medium and large effect sizes. For a plausibility of 10%, the TRP were 16.1%, 40.8% and 58.5%. These results generalize to a subfield of animal-model experimental psychopharmacoloy (nicotine CPP in mice) the lack of power reported in the litterature of several neurobehavioural and psychological disciplines

LES RÉSULTATS DE LA RECHERCHE CLINIQUE EN NEUROPSYCHOLOGIE SONT-ILS UTILISABLES ? UNE ANALYSE MÉTA-SCIENTIFIQUE

editorial reviewe

Effects of α-synuclein levels on cerebral synaptic function: Validation of a novel PET radioligand for the early diagnosis of Parkinson’s disease

Background In Parkinson’s disease, converging evidence supports a pathogenic role for excessive α–synuclein accumulation in synaptic terminals that may propagate back to the soma of vulnerable nerve cells such as neurons in the substantia nigra pars compacta. The resulting loss of dopaminergic terminals in the striatum can be demonstrated in vivo using 18F-Dopa-PET (positron emission tomography). However, there’s currently no validated biomarker of the progressive synaptic dysfunction in other vulnerable areas such as the cerebral cortex. Goal In this longitudinal study, we will test the hypothesis that the loss of synaptic terminals in a mouse model of excessive α–synuclein accumulation can be demonstrated in vivo before the occurrence of behavioural disturbances using 18F-UCB-H, a new PET biomarker developed at CRC. We will also test if this new imaging modality is sensitive enough to study the effect of a disease modifying therapy such as chronic physical exercise. Methods We will use microPET for the in vivo quantification of 18F-UCB-H brain uptake in 16 wild type animals and 16 transgenic (Tg) mice overexpressing human α–syn under the mThy1 promotor every 2 months. Data will be validated against post-mortem analyses after the last PET study. Predictions We predict decreased tracer uptake over time in the basal ganglia and cerebral cortex in Tg mice as compared with WT animals. Also, we predict a relationship between 18F-UCB-H uptake levels in basal ganglia and cerebral cortex and progressive alterations in both motor and cognitive functions, respectively. Further, we also expect that chronic exercise will slow down both motor and cognitive disturbances, as well as the rate of 18F-UCB-H brain uptake decreases. Conclusion If 18F-UCB-H PET proves to be a valid biomarker for the early detection of α–synuclein accumulation in the pre-clinical model of PD, the methods will tested on human clinical populations

Exposure to magnetic fields and childhood leukemia: a systematic review and meta-analysis of case-control and cohort studies.

peer reviewedThe association between childhood leukemia and extremely low frequency magnetic fields (ELF-MF) generated by power lines and various electric appliances has been studied extensively during the past 40 years. However, the conditions under which ELF-MF represent a risk factor for leukemia are still unclear. Therefore, we have performed a systematic review and meta-analysis to clarify the relation between ELF-MF from several sources and childhood leukemia. We have systematically searched Medline, Scopus, Cochrane Database of Systematic Review and DARE to identify each article that has examined the relationship between ELF-MF and childhood leukemia. We have performed a global meta-analysis that takes into account the different measures used to assess magnetic field exposure: magnetic flux density measurements (0.2 µT), distances between the child's home and power lines (>200 m vs. 0.4 µT: pooled OR=1.37; 95% CI 1.05-1.80; acute lymphoblastic leukemia alone: seven studies, >0.4 µT: pooled OR=1.88; 95% CI 1.31-2.70). Lower magnetic fields were not associated with leukemia (12 studies, 0.1-0.2 µT: pooled OR=1.04; 95% CI 0.88-1.24; 0.2-0.4 µT: pooled OR=1.07; 95% CI 0.87-1.30). Our meta-analyses based only on distances (five studies) showed that the pooled ORs for living within 50 m and 200 m of power lines were 1.11 (95% CI 0.81-1.52) and 0.98 (95% CI 0.85-1.12), respectively. The pooled OR for living within 50 m of power lines and acute lymphoblastic leukemia analyzed separately was 1.44 (95% CI 0.72-2.88). Our meta-analyses based only on wire codings (five studies) indicated that the pooled OR for the very high current configuration (VHCC) was 1.23 (95% CI 0.72-2.10). Finally, the risk of childhood leukemia was increased after exposure to electric blankets (four studies, pooled OR=2.75; 95% CI 1.71-4.42) and, to a lesser extent, electric clocks (four studies, pooled OR=1.27; 95% CI 1.01-1.60). Our results suggest that ELF-MF higher than 0.4 µT can increase the risk of developing leukemia in children, probably acute lymphoblastic leukemia. Prolonged exposure to electric appliances that generate magnetic fields higher than 0.4 µT like electric blankets is associated with a greater risk of childhood leukemia

Multi- and Transgenerational Outcomes of an Exposure to a Mixture of Endocrine-Disrupting Chemicals (EDCs) on Puberty and Maternal Behavior in the Female Rat.

peer reviewedBACKGROUND: The effects of endocrine-disrupting chemicals (EDCs) on fertility and reproductive development represent a rising concern in modern societies. Although the neuroendocrine control of sexual maturation is a major target of EDCs, little is known about the potential role of the hypothalamus in puberty and ovulation disruption transmitted across generations. OBJECTIVES: We hypothesized that developmental exposure to an environmentally relevant dose of EDC mixture could induce multi- and/or transgenerational alterations of sexual maturation and maternal care in female rats through epigenetic reprograming of the hypothalamus. We investigated the transmission of a disrupted reproductive phenotype via the maternal germline or via nongenomic mechanisms involving maternal care. METHODS: Adult female Wistar rats were exposed prior to and during gestation and until the end of lactation to a mixture of the following 13 EDCs: di-n-butyl phthalate (DnBP), di(2-ethylhexyl) phthalate (DEHP), bisphenol A (BPA), vinclozolin, prochloraz, procymidone, linuron, epoxynaxole, dichlorodiphenyldichloroethylene, octyl methoxynimmate, 4-methylbenzylidene camphor (4-MBC), butylparaben, and acetaminophen. Perinatally exposed offspring (F1) were mated with unexposed males to generate germ cell (F2) and transgenerationally exposed (F3 and F4) females. Sexual maturation, maternal behavior, and hypothalamic targets of exposure were studied across generations. RESULTS: Germ cell (F2) and transgenerationally (F3) EDC-exposed females, but not F1, displayed delayed pubertal onset and altered folliculogenesis. We reported a transgenerational alteration of key hypothalamic genes controlling puberty and ovulation (Kiss1, Esr1, and Oxt), and we identified the hypothalamic polycomb group of epigenetic repressors as actors of this mechanism. Furthermore, we found a multigenerational reduction of maternal behavior (F1-F3) induced by a loss in hypothalamic dopaminergic signaling. Using a cross-fostering paradigm, we identified that the reduction in maternal phenotype was normalized in EDC-exposed pups raised by unexposed dams, but no reversal of the pubertal phenotype was achieved. DISCUSSION: Rats developmentally exposed to an EDC mixture exhibited multi- and transgenerational disruption of sexual maturation and maternal care via hypothalamic epigenetic reprogramming. These results raise concerns about the impact of EDC mixtures on future generations. https://doi.org/10.1289/EHP8795

Wheel-running exercise during adolescence does not substantially affect cocaine conditioned place preference in male C57BL/6J mice

Epidemiological studies suggest that physical exercise could have preventive properties against drugs of abuse vulnerability. Animal research showed that rats or mice housed with a running wheel (a model of aerobic exercise) can exhibit attenuated drug self-administration or drug-induced psychomotor hyperactivity in comparison with their sedentary counterparts. However, the few experiments using conditioned place preference (CPP) are conflicting (positive, negative or null effects of exercise). Aspects or deficiencies of the methods used in some studies, in particular the low sample size (median n=8), the absence of a baseline pre-conditioning session or a control group in the design or (when present) in the data analyses, make the whole picture of results difficult to understand, a situation which warrants further studies, possibly of a better quality than the previous ones. Objectives. Our purpose was to test whether wheel-running exercise during adolescence could impact the formation and long-term retention of CPP to cocaine in mice. Method. Male C57BL/6J mice were individually housed either with (n=32) or without (n=32) a running wheel from 35 days of age. Behavioral testing begun 3 weeks after such housing, all animals being first tested under saline for their baseline preference (white or black compartments). Then, mice underwent 10 once-daily conditioning sessions receiving peritoneal injections of 10 mg/kg cocaine and saline on alternate days (n=16). The white compartment (always non-preferred) was systematically associated to cocaine effects. Control mice received saline every day (n=16). One and 21 days after the last conditioning session, mice were tested for place preference under saline. CPP scores were analyzed with a priori single (cocaine vs saline) and crossed contrasts (testing the housing-by-drug interaction). Each contrast (t-test) incorporated the mean-square error (MSE) provided by a preliminary two-way fixed-model 2x2 ANOVA incorporating the housing condition (2 levels) and the drug treatment (2 levels) as between-group factors and time of testing as a blocking factor (8 levels). Estimates of effect sizes were provided by Cohen’s d calculated from ts and degree of freedom. Results. The two groups exhibited significant well-marked cocaine-induced CPP in both 1-day (d = 1.38 and d = 1.11 at ps < .001 one-tailed in exercised and sedentary mice) and 21-day post-conditioning tests (d = 1.09 and d = 1.15 at ps < .001 one-tailed in exercised and sedentary mice). The (small) effects underlying interaction between housing and the drug treatment were not significant for 1-day (d = 0.19 at p = .48 two-tailed; 95% CI -0.35 to 0.73) or 21-day post-conditioning tests (d = 0.05 at p = .87 two-tailed; 95% CI -0.49 to 0.59). Conclusion. If physical exercise in rodents “truly” impacts CPP induced by drugs of abuse under comparable experimental parameters - as suggested by some studies (either positively or negatively) -, our results indicate that the size of such effects may be quite small, an information rarely reported in the literature

Long-term protective effect of wheel-running on cocaine reactivity

Chronic running activity performed during adolescence in C57BL/6J mice induce a protective long term effect on psycho-stimulating effect of cocain