Adolescent Ethanol Exposure Leads to Stimulus-Specific Changes in Cytokine Reactivity and Hypothalamic-Pituitary-Adrenal Axis Sensitivity in Adulthood

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.

Trends in the use of mind-altering drugs among European adolescents during the Great Recession

“…It is well-known that drug use and abuse during adolescence is associated with long-term deficits in neurodevelopment such as a decline in gray matter volume, dysfunctions in memory and learning ability, and neural changes (39). Previous lab-experiments on rats show that the exposure to ethanol, which is used in the preparation of solvents, reduced their response to stress and immune challenges (40), increasing their deficits in risk-decision making (41). Moreover, the rising use of cocaine and inhalants during a period of economic recession encourages us to speculate on additional potential costs for the economy driven by health costs.…”

Assessment of Extracellular Cytokines in the Hippocampus of the Awake Behaving Rat Using Large‐Molecule Microdialysis Combined with Multiplex Arrays After Acute and Chronic Ethanol Exposure

“…For Experiment 1, adult male Sprague Dawley rats (280 to 320 g) were ordered from Harlan (Frederick, MD) and allowed 2 weeks to acclimate to the colony (22 ± 1°C with 12:12 light–dark cycle, lights on 0700) prior to experimental manipulation. To prevent the confounding stress effects of early‐life shipping, rats for Experiment 2 (also male Sprague Dawley) were bred in our colony at Binghamton University as described elsewhere (Vore et al., ), weaned at postnatal day 21 (P21), and housed in pairs with nonlittermates. To control for litter effects, no more than 1 pup from each litter was assigned to a given experimental condition.…”

“…Rats were exposed to the adolescent CIE paradigm previously employed in our published work (Vore et al., ), an adapted and extended exposure paradigm based on that used by Dr. Toni Pak (e.g., Torcaso et al., ). Chronic exposure was initiated on P33 to P35 and consisted of a total of 4 cycles of EtOH exposure through P53 to P55.…”

“…In particular, brain cytokine responses to acute EtOH administration, as well as stress and immune challenge, were severely blunted in adolescents as compared to adult counterparts (Doremus‐Fitzwater et al., ; Girard‐Joyal et al., ). Recent work from our laboratory indicates that chronic intermittent EtOH exposure during this adolescent time period (adolescent CIE) resulted in a locking‐in‐like immune effect, wherein animals exposed to adolescent CIE displayed an impaired cytokine response in white blood cells when challenged with either lipopolysaccharide (LPS) or acute restraint in adulthood (Vore et al., ). Given the emergent role for neuroimmune signaling in the development of alcohol addiction and alcohol‐related brain pathology, it is of importance to expand our understanding of these locking‐in‐like effects and their level of contribution to the maladaptive drinking patterns induced by adolescent EtOH exposure.…”

Maternal high-fat diet induces sex-specific changes to glucocorticoid and inflammatory signaling in response to corticosterone and lipopolysaccharide challenge in adult rat offspring

“…A 10mg/kg dose of CORT was previously shown to lead to heightened anxiety-like behaviour (Mitra and Sapolsky, 2008) and circulating plasma CORT levels similar to that of several hours of acute physiological stress (Stein-Behrens et al, 1994). The 50 μg/kg dose of LPS was shown to activate the HPA axis within 0.5-4 h, as shown by increased CORT levels in whole-blood (Vore et al, 2017) and induce proinflammatory cytokine expression in the hippocampus of offspring exposed to maternal HFD (Bilbo and Tsang, 2010). Animals were sacrificed 3 h post injection by CO2 inhalation followed by rapid decapitation at the mid-point of the light phase (11-3 pm) to control for circadianrelated changes in gene expression.…”