ABSTRACT
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.
ABSTRACT
BACKGROUND: Beyond the well-known deleterious effects of ethanol defining Fetal Alcohol Spectrum Disorders (FASD), the notion of fetal alcohol programming has gained scientific support. This phenomenon implies early neural plasticity relative to learning mechanisms comprising ethanol´s sensory cues and physiological effects of the drug; among others, its reinforcing properties and its depressant effects upon respiration. In this study, as a function of differential ethanol exposure during gestation, we analyzed neonatal physiological and behavioral responsiveness recruited by the odor of the drug. METHODS: A factorial design defined by maternal ethanol intake during pregnancy (Low, n = 38; Moderate, n = 18 or High, n = 19) and olfactory stimulation (ethanol odor and/or or a novel scent) served as the basis of the study. Neonatal respiratory and cardiac frequencies, oxygen saturation levels and appetitive or aversive facial expressions, served as dependent variables. RESULTS: Newborns of High drinkers exhibited significant physiological and behavioral signs indicative of alcohol odor recognition; specifically, respiratory depressions and exacerbated appetitive facial reactions coupled with diminished aversive expressions. Respiratory depressions were not accompanied by heart rate accelerations (cardiorespiratory dysautonomia). According to ROC curve analyses respiratory and behavioral reactivity were predictive of high maternal intake patterns. CONCLUSIONS: These results validate the notion of human fetal alcohol programming that is detected immediately after birth. The reported early functional signs indicative of relatively high alcohol gestational exposure should broaden our capability of diagnosing FASD and lead to appropriate primary or secondary clinical interventions (Registry of Health Research N.3201- RePIS, Córdoba, Argentina).
ABSTRACT
The anatomo-physiological disruptions inherent to different categories of the Fetal Alcohol Spectrum Disorder do not encompass all the negative consequences derived from intrauterine ethanol (EtOH) exposure. Preclinical, clinical and epidemiological studies show that prenatal EtOH exposure also results in early programming of alcohol affinity. This affinity has been addressed through the examination of how EtOH prenatally exposed organisms recognize and prefer the drug's chemosensory cues and their predisposition to exhibit heightened voluntary EtOH intake during infancy and adolescence. In altricial species these processes are determined by the interaction of at least three factors during stages equivalent to the 2nd and 3rd human gestational trimester: (i) fetal processing of the drug's olfactory and gustatory attributes present in the prenatal milieu; (ii) EtOH's recruitment of central reinforcing effects that also imply progressive sensitization to the drug's motivational properties; and (iii) an associative learning process involving the prior two factors. This Pavlovian learning phenomenon is dependent upon the recruitment of the opioid system and studies also indicate a significant role of EtOH's principal metabolite (acetaldehyde, ACD) which is rapidly generated in the brain via the catalase system. The central and rapid accumulation of this metabolite represents a major factor involved in the process of fetal alcohol programming. According to recent investigations, it appears that ACD exerts early positive reinforcing consequences and antianxiety effects (negative reinforcement). Finally, this review also acknowledges human clinical and epidemiological studies indicating that moderate and binge-like drinking episodes during gestation result in neonatal recognition of EtOH's chemosensory properties coupled with a preference towards these cues. As a whole, the studies under discussion emphasize the notion that even subteratogenic EtOH exposure during fetal life seizes early functional sensory and learning capabilities that pathologically shape subsequent physiological and behavioral reactivity towards the drug.
ABSTRACT
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 respiratory plasticity. The present study analyzed physiological and behavioral effects of early central administrations of ethanol, acetaldehyde or vehicle. Respiration rates (breaths/min) were registered at post-natal days (PDs) 2 and 4 (post-administration time: 5, 60, or 120 min). At PD5, all pups were placed in a context (plethysmograph) where they had previously experienced the effects of central administrations and breathing patterns were recorded. Following this test, pups were evaluated using and operant conditioning procedure where ethanol or saccharin served as positive reinforcers. Body temperatures were also registered prior to drug administrations as well as at the beginning and the end of each specific evaluation. Across days, breathing responses were high at the beginning of the evaluation session and progressively declined as a function of the passage of time. At PDs 2 and 4, shortly after central administration (5 min), ACD exerted a significant depression upon respiration frequencies. At PD5, non-intoxicated pups with a prior history of ACD central administrations, exhibited a marked increase in respiratory frequencies; a result that probably indicates a conditioned compensatory response. When operant testing procedures were conducted, prior ethanol or ACD central administrations were found to reduce the reinforcing effects of ethanol. This was not the case when saccharin was employed as a reinforcer. As a whole, the results indicate a significant role of central ACD upon respiratory plasticity of the neonate and upon ethanol's reinforcing effects; phenomena that affect the physiological integrity of the immature organism and its subsequent affinity for ethanol operationalized through self-administration procedures.
ABSTRACT
Drugs of abuse, as cocaine or amphetamine, induce locomotor sensitization during infancy and adulthood of the rat. This effect during the preweanling period is observed only after a short interval of time between training and testing. We recently reported short-term locomotor sensitization induced by ethanol in pups chronically exposed to the drug during the second postnatal week of life. The present series of experiments was designed to explore the persistence of the sensitization effect across the preweanling period. Pups were chronically exposed to ethanol in five consecutive days during the second or the third postnatal weeks, and their locomotor activity was evaluated in an open field 3, 8 or 15days later. Our results showed that, contrarily to what has been observed with other drugs during infancy, sensitization to ethanol persisted at least 8days in rats exposed to the drug during the second postnatal week. Surprisingly, in older pups, the same procedure induced tolerance instead sensitization. This ontogenetic model offers a potentially interesting tool for studying within the same species, how tolerance and sensitization are interrelated, and how these effects affect ethanol-mediated reinforcement and ethanol intake during ontogeny.
