Ethanol neurobehavioural teratogenicity in the guinea pig: The pathophysiological involvement of the glucocorticoid signaling pathway in the hippocampus and the use of behavioural intervention as a treatment strategy

Chronic excessive maternal drinking of ethanol during pregnancy can produce teratogenic effects that are collectively termed fetal alcohol spectrum disorders (FASD), including fetal alcohol syndrome (FAS). The mechanism of ethanol neurobehavioural teratogenicity appears to be multi-faceted. It is postulated that disruption of the hypothalamic-pituitary-adrenal (HPA) axis, leading to increased fetal cortisol concentration is an important contributor to ethanol neurobehavioural teratogenicity. This hypothesis was tested in the guinea pig, an established animal model of ethanol teratogenicity. Chronic prenatal ethanol exposure (CPEE) activated the maternal and the near-term fetal HPA axis producing increased adrenocorticotropic hormone (ACTH) and cortisol concentrations in the fetal systemic blood circulation. In the near-term fetus, CPEE increased the sensitivity of the hippocampus to high-glucocorticoid-concentration-induced basal glutamate release, which was temporally associated with increased glucocorticoid receptor mRNA expression. As well, CPEE increased stimulated glutamate release and NMDA receptor mRNA expression in the near-term fetal hippocampus. This CPEE-induced fetal hypercortisolemia was associated with long-lasting changes in glucocorticoid signaling in adult postnatal offspring, which manifested as attenuation of low-glucocorticoid-concentration-induced suppression of hippocampal stimulated glutamate release, and as increased saliva cortisol concentration in response to swim stress. CPEE produced performance deficits in a stationary-hidden-platform Morris water-maze behavioural task that were associated with delayed acquisition of appropriate behavioural strategies, but not with any neuroendocrine effects. Behavioural intervention, in the form of non-spatial pre-training, mitigated the CPEE-induced water maze performance deficits, although the more challenging moving-hidden-platform water-maze task continued to reveal cognitive deficits. Innovative treatment strategies, involving both behavioural intervention and pharmacological treatment, may prove to be the most successful approach for treating ethanol neurobehavioural teratogenicity.