Conditioned effects of ethanol on the immune system

Several studies indicate that the immune system can be subjected to classical conditioning. Acute ethanol intoxication significantly modulates several pro-inflammatory cytokines (e.g. interleukins-1 and 6 [IL-1β and IL-6, respectively] and tumor necrosis factor alpha [TNFα])) in several brain areas, including amygdala (AMG), paraventricular nucleus (PVN), and hippocampus (HPC). It is unknown, however, whether cues associated with ethanol can elicit conditioned alterations in cytokine expression. The present study analyzed, in male Sprague-Dawley rats, whether ethanol-induced changes in the central cytokine response may be amenable to conditioning. In Experiments 1 and 2, the rats were given one or two pairings between a distinctive odor (conditional stimulus, CS) and the post-absorptive effects of a high (3.0 or 4.0 g/kg, Experiments 1 and 2, respectively) ethanol dose. Neither of these experiments revealed conditioning of IL-6, IL-1β, or TNFα, as measured via mRNA levels. Yet, re-exposure to the lemon-odor CS in Experiment 1 significantly increased C-Fos levels in the PVN. In Experiment 3, the rats were given four pairings between an odor CS and a moderate ethanol dose (2.0 g/kg), delivered intraperitoneally (i.p.) or intragastrically (i.g.). Re-exposure to the odor CS significantly increased IL-6 levels in HPC and AMG, an effect only evident in paired rats administered ethanol i.p. Overall, this study suggests that ethanol exposure can regulate the levels of IL-6 at HPC and AMG via classical conditioning mechanisms. These ethanol-induced, conditioned alterations in cytokine levels may ultimately affect the intake and motivational effects of ethanol. Impact statement: This study examines, across three experiments, whether odor cues associated with ethanol exposure can condition changes in cytokine expression. The analysis of ethanol-induced conditioning of immune responses is a novel niche that can help understand the transition from social drinking to alcohol abuse and dependence. Ethanol-induced conditioning of the immune system could likely exacerbate neuroinflammation and drug-related toxicity, which in turn may facilitate further engagement in ethanol intake. The main new finding of the present study was that, after four pairings of ethanol’s unconditioned effects and a distinctive odor, the latter CS increased IL-6 levels in HPC and AMG. This suggests that ethanol’s effects upon IL-6 in HPC and AMG may come under conditioned control, particularly after repeated pairings between distinctive odor cues and ethanol’s effects. This article advances our knowledge of conditioned increases in cytokine responses, which should help understand the mechanisms underlying alcohol use, abuse, and relapse.Fil: Gano, Anny. Developmental Exposure Alcohol Research Center; Estados UnidosFil: Pautassi, Ricardo Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Doremus-Fitzwater, Tamara L. Ithaca College; Estados UnidosFil: Deak, Terrence. Developmental Exposure Alcohol Research Center; Estados Unido

Conditioning the neuroimmune response to ethanol using taste and environmental cues in adolescent and adult rats

Our work in adult Sprague-Dawley rats has shown elevation of the cytokine Interleukin (IL)-6 in the hippocampus and amygdala following acute and repeated binge-like doses of ethanol during intoxication. Previously, we have shown that in adults, the central IL-6 response to a sub-threshold dose of ethanol was sensitized by repeated pairings of ethanol as an unconditioned stimulus (US) with an odor conditioned stimulus (CS).In the present studies, acute ethanol exposure (4 g/kg intraperitoneal) was paired with a combined odor and taste cue using a single trial learning procedure, after which rats were tested for conditioned effects of the CS on neuroimmune gene expression. We found that IL-6 was significantly elevated in the amygdala based on exposure to the CS after just one CS–US pairing in young adolescent rats (age P32–40), an effect that was more modest in young adults (P72–80). These data indicate that, despite a normal disposition toward a blunted neuroimmune response to ethanol, adolescents were more sensitive than adults to forming learned associations between ethanol’s neuroimmune effects and conditioned stimuli. Given the emergent role of the immune system in alcoholism, such as regulating ethanol intake, these ethanol-induced conditioned effects on cytokine levels may contribute to our understanding of the unique attributes that make adolescence a time period of vulnerability in the development of later alcohol abuse behaviors. Impact statement: A combined odor and taste cue was paired with a binge-like ethanol exposure (4 g/kg intraperitoneal) using a single-trial learning paradigm. Re-exposure to the CS alone was sufficient to evoke a conditioned Interleukin (IL)-6 elevation in the amygdala in adolescents, an effect that was not observed in young adults. This demonstrates a particular sensitivity of adolescents to alcohol-associated cues and neuroimmune learning, whereas prior work indicated that adults require multiple pairings of ethanol to the CS in order to achieve a conditioned amygdala IL-6 response. While the role of immune conditioning has been studied in other drugs of abuse, these findings highlight a previously unknown aspect of alcohol-related learning. Given the emergent importance of the neuroimmune system in alcohol abuse, these findings may be important for understanding cue-induced reinstatement of alcohol intake among problem drinkers.Fil: Gano, Anny. University Of Binghamton. Departament Of Psychology; Estados UnidosFil: Pautassi, Ricardo Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Doremus-Fitzwater, Tamara L.. University Of Binghamton. Departament Of Psychology; Estados UnidosFil: Barney, Thaddeus M.. University Of Binghamton. Departament Of Psychology; Estados UnidosFil: Vore, Andrew S.. University Of Binghamton. Departament Of Psychology; Estados UnidosFil: Deak, Terrence. University Of Binghamton. Departament Of Psychology; Estados Unido

Neurobehavioral alterations induced by third-trimester gestation-equivalent ethanol exposure are inhibited by folate administration

Prenatal ethanol exposure (PEE) causes several neurobehavioral impairments in the fetus. Postnatal days (PDs) 4-9 in rodents are considered equivalent to the third trimester of gestation in humans. This period is characterized by high rates of synaptogenesis and myelination and the maturation of key structures and transmitter systems. Nutritional supplements, such as folate, have gained attention as putative treatments to mitigate detrimental effects of PEE. Folate is crucial for DNA synthesis and amino acid metabolism and heightens antioxidant defenses. The present study examined neurobehavioral effects of the concurrent administration of folate (20 mg/kg/day) and ethanol (5 g/kg/day) during PDs 4-9 in male and female Wistar rats. During PDs 16-18, the rat pups were tested for anxiety-like and exploratory activity in the light-dark box (LDB), open field (OF), and concentric square field (CSF) tests. After weaning, they were tested for sucrose preference and ethanol intake. Neonatal ethanol exposure reduced body weight in infancy but did not enhance ethanol self-administration or significantly affect performance in the OF or LDB. Neonatal ethanol exposure also reduced sucrose intake in the preference test and increased shelter-seeking in the CSF, and folate significantly inhibited these effects. The present findings suggest that folate, a treatment that is devoid of serious side effects, can ameliorate some neurobehavioral effects of PEE

Highlight Article: Conditioning the neuroimmune response to ethanol using taste and environmental cues in adolescent and adult rats

© 2019 by the Society for Experimental Biology and Medicine. Our work in adult Sprague-Dawley rats has shown elevation of the cytokine Interleukin (IL)-6 in the hippocampus and amygdala following acute and repeated binge-like doses of ethanol during intoxication. Previously, we have shown that in adults, the central IL-6 response to a sub-threshold dose of ethanol was sensitized by repeated pairings of ethanol as an unconditioned stimulus (US) with an odor conditioned stimulus (CS).In the present studies, acute ethanol exposure (4 g/kg intraperitoneal) was paired with a combined odor and taste cue using a single trial learning procedure, after which rats were tested for conditioned effects of the CS on neuroimmune gene expression. We found that IL-6 was significantly elevated in the amygdala based on exposure to the CS after just one CS–US pairing in young adolescent rats (age P32–40), an effect that was more modest in young adults (P72–80). These data indicate that, despite a normal disposition toward a blunted neuroimmune response to ethanol, adolescents were more sensitive than adults to forming learned associations between ethanol’s neuroimmune effects and conditioned stimuli. Given the emergent role of the immune system in alcoholism, such as regulating ethanol intake, these ethanol-induced conditioned effects on cytokine levels may contribute to our understanding of the unique attributes that make adolescence a time period of vulnerability in the development of later alcohol abuse behaviors. Impact statement: A combined odor and taste cue was paired with a binge-like ethanol exposure (4 g/kg intraperitoneal) using a single-trial learning paradigm. Re-exposure to the CS alone was sufficient to evoke a conditioned Interleukin (IL)-6 elevation in the amygdala in adolescents, an effect that was not observed in young adults. This demonstrates a particular sensitivity of adolescents to alcohol-associated cues and neuroimmune learning, whereas prior work indicated that adults require multiple pairings of ethanol to the CS in order to achieve a conditioned amygdala IL-6 response. While the role of immune conditioning has been studied in other drugs of abuse, these findings highlight a previously unknown aspect of alcohol-related learning. Given the emergent importance of the neuroimmune system in alcohol abuse, these findings may be important for understanding cue-induced reinstatement of alcohol intake among problem drinkers