Figure - available from: Frontiers in Behavioral Neuroscience
This content is subject to copyright.
Breathing rates (breaths/min) as a function of drug treatment (PB, ACD, or Ethanol) and minutes of evaluation at PD 5. * Indicates significant differences between ACD pups and pups pre-exposed to PB administrations. Vertical lines indicate standard errors of the means (SEMs).
Source publication
Prior studies indicate that neonates are very sensitive to ethanol's positive reinforcing effects and to its depressant effects upon breathing. Acetaldehyde (ACD) appears to play a major role in terms of modulating early reinforcing effects of the drug. Yet, there is no pre-existing literature relative to the incidence of this metabolite upon respi...
Similar publications
The oxidative metabolism of ethanol into acetaldehyde involves several enzymes, including alcohol dehydrogenase (ADH) and catalase-hydrogen peroxide (H2O2). In this regard, while it is well known that 4-methylpyrazole (4-MP) acts by inhibiting ADH in the liver, little attention has been placed on its ability to interfere with fatty acid oxidation-m...
Citations
... Under the present experimental conditions, we were unable to observe a role of gestational acetaldehyde upon respiratory plasticity or affective state of the organisms. To our knowledge, there is one study that reports respiratory depressions following acetaldehyde central administration 5 minutes, but not 60 or 120 after (Acevedo et al., 2017b). As to the role of acetaldehyde in the modulation of ethanol's affective state, the results in adult rodents are controversial and seem to depend on factors such as the dose, route of administration, or animal strain. ...
Early ontogeny of the rat (late gestation and postnatal first week) is a sensitive period to ethanol’s positive reinforcing effects and its detrimental effects on respiratory plasticity. Recent studies show that acetaldehyde, the first ethanol metabolite, plays a key role in the modulation of ethanol motivational effects. Ethanol brain metabolization into acetaldehyde via the catalase system appears critical in modulating ethanol positive reinforcing consequences. Catalase system activity peak levels occur early in the ontogeny. Yet, the role of ethanol-derived acetaldehyde during the late gestational period on respiration response, ultrasonic vocalizations (USVs), and ethanol intake during the first week of the rat remains poorly explored. In the present study, pregnant rats were given a subcutaneous injection of an acetaldehyde-sequestering agent ( D -penicillamine, 50 mg/kg) or saline (0.9% NaCl), 30 min prior to an intragastric administration of ethanol (2.0 g/kg) or water (vehicle) on gestational days 17–20. Respiration rates (breaths/min) and apneic episodes in a whole-body plethysmograph were registered on postnatal days (PDs) 2 and 4, while simultaneously pups received milk or ethanol infusions for 40-min in an artificial lactation test. Each intake test was followed by a 5-min long USVs emission record. On PD 8, immediately after pups completed a 15-min ethanol intake test, brain samples were collected and kept frozen for catalase activity determination. Results indicated that a moderate experience with ethanol during the late gestational period disrupted breathing plasticity, increased ethanol intake, as well brain catalase activity. Animals postnatally exposed to ethanol increased their ethanol intake and exerted differential affective reactions on USVs and apneic episodes depending on whether the experience with ethanol occur prenatal or postnatally. Under the present experimental conditions, we failed to observe, a clear role of acetaldehyde mediating ethanol’s effects on respiratory plasticity or affective states, nevertheless gestational acetaldehyde was of crucial importance in determining subsequent ethanol intake affinity. As a whole, results emphasize the importance of considering the participation of acetaldehyde in fetal programming processes derived from a brief moderate ethanol experience early in development, which in turn, argues against “safe or harmless” ethanol levels of exposure.
... Non-associative learning processes have been observed when considering EtOH's detrimental effects upon respiration. Progressive sensitization to the depressant effects of EtOH upon respiration have been reported in altricial mammals during stages equivalent to the 2nd and 3rd human gestational trimesters in terms of synaptogenesis (Acevedo et al., 2017a;Acevedo et al., 2017b;Cullere et al., 2015;D'aloisio et al., 2020;Macchione et al., 2016Macchione et al., , 2018. Different environmental factors, such as early EtOH exposure and unstable perinatal oxygen air conditions, may also influence fetal and neonatal respiratory development (Bisgard et al., 2003). ...
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.
... In the case of the first two modes of administration, the organism exhibits a subsequent unconditioned breathing depression that was also corroborated during the conditioning phase of the present experiment. When the administration procedure is not temporally associated with breathing evaluations within the plethysmograph (unpaired condition), respiratory frequencies are noticeable higher (Acevedo et al. 2017a). In this study, unpaired treatments were defined by a 2.5-h delay between pleth placement and the corresponding administration procedure. ...
Rationale:
The effects of early ethanol exposure upon neonatal respiratory plasticity have received progressive attention given a multifactorial perspective related with sudden infant death syndrome or hypoxia-associated syndromes. The present preclinical study was performed in 3-9-day-old pups, a stage in development characterized by a brain growth spurt that partially overlaps with the 3rd human gestational trimester.
Methods:
Breathing frequencies and apneas were examined in pups receiving vehicle or a relatively moderate ethanol dose (2.0 g/kg) utilizing a whole body plethysmograph. The experimental design also considered possible associations between drug administration stress and exteroceptive cues (plethysmographic context or an artificial odor). Ethanol exposure progressively exerted a detrimental effect upon breathing frequencies. A test conducted at PD9 when pups were under the state of sobriety confirmed ethanol's detrimental effects upon respiratory plasticity (breathing depression).
Results:
Pre-exposure to the drug also resulted in a highly disorganized respiratory response following a hypoxic event, i.e., heightened apneic episodes. Associative processes involving drug administration procedures and placement in the plethysmographic context also affected respiratory plasticity. Pups that experienced intragastric administrations in close temporal contiguity with such a context showed diminished hyperventilation during hypoxia. In a 2nd test conducted at PD9 while pups were intoxicated and undergoing hypoxia, an attenuated hyperventilatory response was observed. In this test, there were also indications that prior ethanol exposure depressed breathing frequencies during hypoxia and a recovery normoxia phase.
Conclusion:
As a whole, the results demonstrated that brief ethanol experience and stress-related factors significantly disorganize respiratory patterns as well as arousal responses linked to hypoxia in neonatal rats.
Fetal ethanol exposure represents a risk factor for the Sudden Infant Death Syndrome and its respiratory effects promote hypoxic ischemic consequences. This study analyzes central ethanol’s effects upon breathing plasticity during an ontogenetic stage equivalent to the third human gestational trimester. Ethanol’s unconditioned breathing effects and their intervention in learning processes were examined. Since central ethanol is primarily metabolized via the catalase system, we also examined the effects of early history with the drug upon this system. During postnatal days 3, 5 and 7 (PDs 3-7) pups were intracisternally administered with vehicle or ethanol (300 mg%). They were tested in a plethysmograph scented or not with ethanol odor. The state of intoxication attenuated the onset of apneas; a phenomenon suggestive of ethanol’s anxiolytic effects given the state of arousal caused by the novel environment and the stress of administrations. At PD9, pups were evaluated sober under sequential air conditions (initial-normoxia, hypoxia and recovery-normoxia) with or without the presence of ethanol odor. Initial apneic episodes increased when ethanol intoxication was previously associated with the odorant. Pups then ingested ethanol and brain catalase activity was determined. Pre-exposure to ethanol intoxication paired with the odor of the drug resulted in heightened enzymatic activity. Central ethanol exposure appears to exert antianxiety effects that attenuate apneic disruptions but under the state of withdrawal, the cues associated with such effects elicit an opposite reaction. The activity of the catalase system was also dependent upon learning processes determined by the association of environmental stimuli and ethanol intoxication.
