Sex difference in the vulnerability to hippocampus plasticity impairment after binge‐like ethanol exposure in adolescent rat: Is estrogen the key?

Abstract

Binge drinking during adolescence induces memory impairments, and evidences suggest that females are more vulnerable than males. However, the reason for such a difference is unclear, whereas preclinical studies addressing this question are lacking. Here we tested the hypothesis that endogenous estrogen level (E2) may explain sex differences in the effects of ethanol on hippocampus plasticity, the cellular mechanism of memory. Long‐term depression (LTD) in hippocampus slice of pubertal female rats was recorded 24 h after two ethanol binges (3 g/kg, i.p., 9 h apart). Neither the estrous cycle nor ethanol altered LTD. However, if ethanol was administered during proestrus (i.e., at endogenous E2 peak), LTD was abolished 24 h later, whereas NMDA‐fEPSPs response to a GluN2B antagonist increased. The abolition of LTD was not observed in adult female rats. Exogenous E2 combined with ethanol replicated LTD abolition in pubertal, prepubertal female, and in pubertal male rats without changes in ethanol metabolism. In male rats, a higher dose of ethanol was required to abolish LTD at 24‐h delay. In pubertal female rats, tamoxifen, an antagonist of estrogen receptors, blocked the impairing effects of endogenous and exogenous E2 on LTD, suggesting estrogen interacts with ethanol through changes in gene expression. In addition, tamoxifen prevented LTD abolition at 24 h but not at 48‐h delay. In conclusion, estrogen may explain the increased vulnerability to ethanol‐induced plasticity impairment seen in females compared with males. This increased vulnerability of female rats is likely due to changes in the GluN2B subunit that represent a common target between ethanol and estrogen.

S-Palmitoylation of Synaptic Proteins as a Novel Mechanism Underlying Sex-Dependent Differences in Neuronal Plasticity

“…Sex-specific changes in spine density were observed in different brain regions, such as the hippocampus, nucleus accumbens, or the prefrontal cortex [63,64]. Moreover, it was shown that estradiol can potentiate excitatory synapses and attenuate inhibitory synapses exclusively in females [58,59,[65][66][67]. In contrast, testosterone appears to inhibit long term potentiation (LTP) and dendritic sprouting in the male hippocampus [68].…”

Coral Hydrate, a Novel Antioxidant, Improves Alcohol Intoxication in Mice

“…In addition, gender difference could affect alcohol intolerance [ 30 ]. Estrogen modulates the ethanol-evoked myocardial oxidative stress and dysfunction [ 31 ] and it also plays a role in the increased vulnerability to ethanol-induced hippocampus plasticity impairment seen in females as compared with males [ 32 ]. In order to exclude the confounding effects of estrogen, we used male mice to evaluate the effects of coral hydrate on ethanol intoxication.…”

Testing the consequences of alcohol, cannabis, and nicotine use on hippocampal volume: a quasi-experimental cotwin control analysis of young adult twins

“…metabolism) or interactions between sex hormones and substance use. Recent experimental work suggests that accelerated changes in hippocampal plasticity have been observed in female but not male rodents at similar doses of ethanol, an effect driven by the presence of high estrogen levels in female rats (Rabiant, Antol, Naassila, & Pierrefiche, 2021 ). Evidence also suggests that some nicotine-related sex differences may be mediated by the influence of sex hormones on nicotine metabolism or craving and contextual processing/reinforcement (Cross, Linker, & Leslie, 2017 ), themselves processes closely related to the hypothesized involvement of the hippocampus in neural circuitry models of substance use/addiction (Koob & Volkow, 2010 , 2016 ).…”