Abstract
Adolescent alcohol use comprises a significant public health concern and is often characterized by binge-like consumption patterns. While ethanol exposure in adulthood has been shown to alter the stress response, including the Hypothalamic–Pituitary–Adrenal (HPA) axis, few studies have examined whether binge-like ethanol exposure during adolescence results in enduring changes in HPA axis sensitivity in adulthood. In the present studies, adolescent Sprague-Dawley rats were given intragastric (i.g.) intubations of ethanol (4 g/kg) or vehicle once per day for three consecutive days, beginning on postnatal day (P) 30 (±1). This exposure was followed by a 2-day period of rest/withdrawal. Rats received a total of either two (Experiments 1, 2 and 3) or four (Experiment 4) cycles of ethanol exposure and were subsequently allowed to age normally until adulthood. In Experiment 1, adult, (P71–75), ethanol- or vehicle-exposed rats received a 60 min restraint stress challenge. In Experiment 2, rats received a 50 μg/kg injection of lipopolysaccharide (LPS). In Experiment 3, rats received a challenge of 2.5 g/kg ethanol (intraperitoneally; i.p.). In Experiment 4, male and female ethanol- or vehicle- exposed rats received a 50 μg/kg injection of LPS. In all experiments, blood samples were collected for later assessment of corticosterone (CORT), blood ethanol concentrations (BECs), and the cellular fraction of blood was analyzed for cytokine gene expression. As expected, all three challenges led to a time-dependent surge in CORT. Gene expression analyses of cytokines (Interleukin [IL]-6, IL-1β, and Tumor necrosis factor alpha [TNFα]) from the cellular fraction of blood revealed unique, time-dependent patterns of cytokine expression depending upon the nature of the adult challenge incurred (restraint, LPS, or EtOH). Importantly, adolescent ethanol exposure led to attenuated restraint and LPS-induced cytokine expression in males, whereas female rats displayed an absence of cytokine alterations, and a tendency toward heightened HPA axis reactivity. These findings suggest that adolescent ethanol exposure may cause lasting alterations in cytokine regulation and HPA axis sensitivity that (a) persist into adulthood; (b) may vary depending on the nature of the challenge incurred during adulthood; and that (c) are sex-specific.
Highlights
Alcohol use and abuse disorders comprise a substantial public health and financial burden, resulting in an estimated 3.3 million deaths per year globally and $223.5 billion in financial burden to the United States alone (Centers for Disease Control and Prevention, 2014; World Health Organization, 2014)
Rats were treated in accordance with Public Health Service (PHS) policy and all experimental protocols were approved by the Institutional Animal Care and Use Committee (IACUC) at Binghamton University
There was a trend indicating that adolescent ethanol exposure increased CORT release following LPS challenge in female rats (F(4,48) = 1.68, p = 0.17), no such effect was seen in male rats (Figures 3B,C)
Summary
Alcohol use and abuse disorders comprise a substantial public health and financial burden, resulting in an estimated 3.3 million deaths per year globally and $223.5 billion in financial burden to the United States alone (Centers for Disease Control and Prevention, 2014; World Health Organization, 2014). Adolescent animals have exhibited increased locomotor sensitization to ethanol and higher sensitivity to the motivational effects of ethanol (Pautassi et al, 2008) compared to adult counterparts that received similar quantities of ethanol. This differential reaction to a spectrum of consequences of ethanol exposure likely contributes to adolescent animals consuming higher quantities of ethanol, since insensitivity to negative consequences of high dose ethanol use (sedation, motor impairment, aversion) and hypersensitivity to various positive elements would seem to promote future ethanol consumption (Varlinskaya and Spear, 2004b)
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