Research reportRepeated cycles of binge-like ethanol exposure induce immediate and delayed neurobehavioral changes and hippocampal dysfunction in adolescent female rats
Introduction
Although ethanol consumption is culturally one of the oldest human habits [1], the abuse of ethanol intake causes both acute behavioral alterations as a well as maladaptive long-term consequences ranging from anxiety and cognitive decline to metabolic disruption and liver failure [2]. Adolescents are at particular risk to initiate ethanol intake and abuse because of their profile of increased impulsivity, risk behavior and searching for novelty as well as a result of their idiosyncratic response to the effects of ethanol typified by their greater sensitivity to the motor stimulant and reward effects rather than to the aversive effects of ethanol [3]; reviewed in [4]). During adolescence, the brain undergoes considerable remodeling, typifieded by an enhanced dopaminergic and glutamatergic transmission and plasticity [5,6]. Thus, the consequences of ethanol consumption in adolescents are also than in adults (e.g [7,8]). probably due to the particular impact of ethanol on the active on-going brain maturation during adolescence [9,10].
The most frequent pattern of ethanol intake by adolescents and young adults is the excessive episodic ethanol consumption known as binge drinking, characterized by days of high intake followed by withdrawal [11]. Studies in South America have concluded that ethanol is most frequently consumed in a binge manner during 3 days a week [12,13]. Binge-like ethanol consumption has immediate consequences such as memory impairments and blackouts, as well as long-term consequences into adulthood such as increased susceptibility to drug abuse, anxiety and sleep disruption, which are present in humans as well as in rodent models of binge-like ethanol treatments [9,10]. These acute effects of binge-ethanol intake in adolescent, some evolving into adulthood psychopathology, have been characterized in males, whereas binge drinking is increasing among women [14]. There are sex differences in response to binge-like ethanol that indicate a greater susceptibility of females to the acute and long-term alterations of mood and memory after ethanol-intermittent treatment [[15], [16], [17]].
Several brain features display sexual dimorphism, amongst which stem, in the context of ethanol intake, brain-derived neurotrophic factor (BDNF) signaling [[18], [19], [20]] and astrocyte function [21,22]. Both mood and hippocampal-dependent memory are dependent on both BDNF signaling [23,24] and glia function [[25], [26], [27]]. Ethanol exposure affects both BDNF [28] and gliosis, encompassing structural and functional modifications of astrocytes and microglia [29].
However, it is still unclear if the exposure of females to ethanol in a binge-like manner causes cumulative effects from middle to late adolescence, if these effects last until adult life and if they might involve astrogliosis or altered BDNF levels. Thus, we now characterized the effects of binge-like ethanol treatment on emotional and cognitive functions from adolescence to adulthood specifically in female rats.
Section snippets
Animals
Adolescent female Wistar rats (n = 112) were derived of 28 litters. Animals were obtained from the Animal Facility of the Federal University of Pará. We used all the females from each litter in this study. Rats were maintained on a 12:12-h light/dark cycle (lights on 7:00 AM), in groups of four rats per cage, with food and water ad libitum. All procedures were approved by the University Ethics Committee (license BIO-196-14) and followed NIH guidelines for the Care and Use of Laboratory Animals.
Blood ethanol levels and evolution of body weight
We first measured the blood ethanol concentrations (BEC) following the binge-like treatments with ethanol. As shown in Table 1, mid-adolescent female rats displayed a BEC of 237.6 ± 16.76 mg/dL at 1 h after the last ethanol administration in a single binge-like ethanol episode (1 cycle ending at PND37), 297.3 ± 34.49 mg/dL at 1 h after 4 cycles (PND58) and 208.0 ± 15.22 mg/dL at 1 h after 8 cycles (at PND 86) and BEC decreased to 0.75 ± 0.48 mg/dL after 7.5 h. These values obtained in
Discussion
The present study fills a gap of knowledge on the neurobehavioral impact of binge-like ethanol exposure specifically in female rats during adolescence up to adulthood. The findings indicate that a single cycle of binge-like ethanol administration produced a pronounced anxiogenic profile in mid-adolescence accompanied by increased levels of GFAP in the hippocampus, whereas multiple cycles of binge drinking during adolescence caused a discrete worsening of memory deterioration and decreased
Funding and disclosure
The authors declare no conflict of interest.
Authors contribution
LMPF, MAB, TCVSC, SCC were responsible for the experimental paradigm design, data acquisition, data analysis and interpretation. MGS, RDP performed the western blot analysis. RAC discussed the project and amended the manuscript. LMPF, RRL, EAFJ, CSFM took part in the conception of the project idea and analyzed and interpreted behavioral data and wrote the manuscript.
Acknowledgements
LMPF received a scholarship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ, Brazil). MAB, TCVSC, SCC received scholarship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil). RDP, MCM are supported by a research fellowship from CNPq. Supported by CAPS-FCT.
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