The Role of Acetaldehyde in the Increased Acceptance of Ethanol after Prenatal Ethanol Exposure

Abstract

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.

Prenatal Alcohol Exposure as a Case of Involuntary Early Onset of Alcohol Use: Consequences and Proposed Mechanisms From Animal Studies

“…The results show that in the absence of acetaldehyde prenatal alcohol, exposure does not induce an increase in postnatal alcohol consumption. These results confirmed that acetaldehyde, and not alcohol, is the main reinforcer and that its production is critical for the occurrence of prenatal appetitive learning about alcohol (Gaztañaga et al, 2017;Chotro et al, 2019). Considering the outcomes of these studies, it could be hypothesized that the reinforcing properties of prenatal alcohol are produced by central acetaldehyde, which in turn stimulates the endogenous opioid system.…”

Fetal Alcohol Programming of Subsequent Alcohol Affinity: A Review Based on Preclinical, Clinical and Epidemiological Studies

“…Brain administration of the drug or its first metabolite was sufficient to promote the rapid acquisition of conditioned olfactory preferences which was markedly inhibited when sequestering central ACD through the use of d-penicillamine (March et al, 2013a,c). A recent study also showed that maternal administration of d-penicillamine significantly decreases the prenatal reinforcing effects of EtOH when considering different levels of expression of alcohol affinity: (i) attractiveness to EtOH odor as assessed through an odor crawling locomotion neonatal test; (ii) operant responding supported by EtOH reinforcement at postnatal day 5; and (iii) EtOH intake during the second postnatal week (Gaztañaga et al, 2017).…”

Early‐lifeexposure to alcohol and the risk ofalcohol‐inducedliver disease in adulthood

“…The fetus develops an appetitive conditional response to alcohol such that it forms an association between the flavor and its pharmacological effects (Bordner & Deak, 2015; Gaztañaga et al, 2020). In the brain, AA, a metabolite produced from the detoxification of alcohol mediates the production of appetitive properties of alcohol as well as serves as its reinforcing agent by acting on the opioid system (Gaztañaga, Angulo‐Alcalde, Spear, & Chotro, 2017). The presence of AA, as well as that of opioid system receptors, is critical in increased alcohol intake.…”

“…The presence of AA, as well as that of opioid system receptors, is critical in increased alcohol intake. Studies show that the absence of AA and the blockade of the opioid system receptors resulted in lower consumption of alcohol (Gaztañaga et al, 2017; Youngentob et al, 2012).…”