Long-term consequences of alcohol use in early adolescent mice: focus on neuroadaptations in GR, CRF and BDNF

Abstract

Our aim was to assess the cognitive and emotional state, as well as related-changes in the glucocorticoid receptor (GR), the corticotropin-releasing factor (CRF) and the brain-derived neurotrophic factor (BDNF) expression of adolescent C57BL/6J male mice after a five-week two-bottle choice protocol (postnatal day (pd) 21 to pd52). Additionally, we wanted to analyse whether the behavioural and neurobiological effects observed in late adolescence (pd62) lasted until adulthood (pd84). Behavioural testing revealed that alcohol during early adolescence increased anxiety-like and compulsive-related behaviours, which was maintained in adulthood. Concerning cognition, working memory was only altered in late adolescent mice, whereas object location test performance was impaired in both ages. In contrast, novel object recognition remained unaltered. Immunohistochemical analysis showed that alcohol during adolescence diminished BDNF+ cells in the cingulate cortex, the hippocampal CA1 layer and the central amygdala. Regarding hypothalamic-pituitary-adrenal axis (HPA) functioning, alcohol abuse increased the GR and CRF expression in the hypothalamic paraventricular nucleus and the central amygdala. Besides this, GR density was also higher in the prelimbic cortex and the basolateral amygdala, regardless of the animals’ age. Our findings suggest that adolescent alcohol exposure led to long-term behavioural alterations, along with changes in BDNF, GR and CRF expression in limbic brain areas involved in stress response, emotional regulation, and cognition.

BDNF and its Role in the Alcohol Abuse Initiated During Early Adolescence: Evidence from Preclinical and Clinical Studies

“…Interestingly, our group observed that controlled treadmill exercise was able to reduce cognitive and emotional alterations in adolescent mice exposed to repeated cycles of binge-like EtOH, whereas the quantity of consumed alcohol was not reduced [ 242 ]. In another study of our group, voluntary running wheel did not reduce the motivational value of alcohol and the drug-seeking responses in a self-administration paradigm conducted in an animal model of ethanol binge-drinking (BD) from adolescence [ 243 ].…”

Altered gut microbiota and metabolites profile are associated with reduced bone metabolism in ethanol‐induced osteoporosis

“…Notably, Chronic, heavy ethanol consumption has been proved to be detrimental to every tissue of the body, which means, despite the direct impairments, ethanol-induced bone loss could be secondary by disrupting metabolic homeostasis of hormones, endogenous metabolites, and nutrient absorption, which are critical for bone forming and growth. 14,15 Several observations have previously suggested that circulating serotonin, as an endogenous metabolite, could be playing a significant role in the regulation of bone mass. 16,17 The Lrp5 gene deficient mice are shown to have high serotonin levels and a low bone mass phenotype.…”

“…Although there is increasing evidence that ethanol plays roles in membrane perturbation and transmembrane signal pathways, the specific subcellular mechanisms whereby inhibit cell proliferation are unknown. Notably, Chronic, heavy ethanol consumption has been proved to be detrimental to every tissue of the body, which means, despite the direct impairments, ethanol‐induced bone loss could be secondary by disrupting metabolic homeostasis of hormones, endogenous metabolites, and nutrient absorption, which are critical for bone forming and growth 14,15 . Several observations have previously suggested that circulating serotonin, as an endogenous metabolite, could be playing a significant role in the regulation of bone mass 16,17 .…”