Adolescent intermittent ethanol (AIE) produces lasting, sex-specific changes in rat body fat independent of changes in white blood cell composition

Early initiation of alcohol use during adolescence, and adolescent binge drinking are risk factors for the development of alcohol use disorder later in life. Adolescence is a time of rapid sex-dependent neural, physiological, and behavioral changes as well as a period of heightened vulnerability to many effects of alcohol. The goal of the present studies was to determine age-related changes in blood (leukocyte populations) and body composition across adolescence and early adulthood, and to investigate whether adolescent intermittent ethanol (AIE) exposure would alter the trajectory of adolescent development on these broad physiological parameters. We observed significant ontogenetic changes in leukocyte populations that were mirrored by an age-related increase in cytokine expression among mixed populations of circulating leukocytes. Despite these developmental changes, AIE did not significantly alter overall leukocyte numbers or cytokine gene expression. However, AIE led to sex-specific changes in body fat mass and fat percentage, with AIE-exposed male rats showing significantly decreased fat levels and female rats showing significantly increased fat levels relative to controls. These changes suggest that while AIE may not alter overall leukocyte levels, more complex phenotypic changes in leukocyte populations could underlie previously reported differences in cytokine expression. Coupled with long-term shifts in adipocyte levels, this could have long-lasting effects on innate immunity and the capacity of individuals to respond to later immunological and physiological threats

Stress alters social behavior and sensitivity to pharmacological activation of kappa opioid receptors in an age-specific manner in Sprague Dawley rats

The dynorphin/kappa opioid receptor (DYN/KOR) system has been identified as a primary target of stress due to behavioral effects, such as dysphoria, aversion, and anxiety-like alterations that result from activation of this system. Numerous adaptations in the DYN/KOR system have also been identified in response to stress. However, whereas most studies examining the function of the DYN/KOR system have been conducted in adult rodents, there is growing evidence suggesting that this system is ontogenetically regulated. Likewise, the outcome of exposure to stress also differs across ontogeny. Based on these developmental similarities, the objective of this study was to systematically test effects of a selective KOR agonist, U-62066, on various aspects of social behavior across ontogeny in non-stressed male and female rats as well as in males and females with a prior history of repeated exposure to restraint (90 min/day, 5 exposures). We found that the social consequences of repeated restraint differed as a function of age: juvenile stress produced substantial increases in play fighting, whereas adolescent and adult stress resulted in decreases in social investigation and social preference. The KOR agonist U-62066 dose-dependently reduced social behaviors in non-stressed adults, producing social avoidance at the highest dose tested, while younger animals displayed reduced sensitivity to this socially suppressing effect of U-62066. Interestingly, in stressed animals, the socially suppressing effects of the KOR agonist were blunted at all ages, with juveniles and adolescents exhibiting increased social preference in response to certain doses of U-62066. Taken together, these findings support the hypothesis that the DYN/KOR system changes with age and differentially responds and adapts to stress across development. Keywords: Juvenile, Adolescent, Adult, Social behavior, Kappa opioid receptor, Restraint stress, Developmen

The Central Reinforcing Properties of Ethanol Are Mediated by Endogenous Opioid Systems: Effects of Mu and Kappa Opioid Antagonists.

Endogenous opioid systems are implicated in the reinforcing effects of ethanol and may play a substantial role in modulating the central reinforcing effects of ethanol early in ontogeny. This possibility was explored in the present study through the use of an olfactory conditioning paradigm with centrally administered ethanol serving as an unconditioned stimulus (US). In Experiment 1, newborn rat pups were treated with either a selective mu antagonist CTOP or kappa selective antagonist nor-BNI prior to olfactory conditioning. Experiment 2 tested the effectiveness of an alternative, shorter-duration kappa opioid antagonist GNTI in altering ethanol reinforcement. Experiment 3 investigated whether the effectiveness of pharmacological blockade of opioid receptors was due to the disruption of learning per se using an olfactory aversive conditioning paradigm with intraoral quinine serving as a US. Central administration of either mu or kappa opioid antagonists prior to conditioning disrupted the reinforcing effects of ethanol in newborn rats. The kappa opioid antagonist GNTI was as effective as nor-BNI. These effects of opioid antagonists on ethanol reinforcement are unlikely to be due to a disruption of all types of conditioning, since CTOP did not affect aversive reinforcement to intraoral infusions of quinine. The present results support the hypothesis that in newborn rats, the reinforcing properties of ethanol are mediated by the endogenous activity at mu and kappa opioid receptors

Las propiedades de refuerzo central del etanol están mediadas por sistemas de opiáceos endógenos: efectos de los antagonistas de los opiáceos Mu y Kappa

Endogenous opioid systems are implicated in the reinforcing effects of ethanol and may play a substantial role in modulating the central reinforcing effects of ethanol early in ontogeny. This possibility was explored in the present study through the use of an olfactory conditioning paradigm with centrally administered ethanol serving as an unconditioned stimulus (US). In Experiment 1, newborn rat pups were treated with either a selective mu antagonist CTOP or kappa selective antagonist nor-BNI prior to olfactory conditioning. Experiment 2 tested the effectiveness of an alternative, shorter-duration kappa opioid antagonist GNTI in altering ethanol reinforcement. Experiment 3 investigated whether the effectiveness of pharmacological blockade of opioid receptors was due to the disruption of learning per se using an olfactory aversive conditioning paradigm with intraoral quinine serving as a US. Central administration of either mu or kappa opioid antagonists prior to conditioning disrupted the reinforcing effects of ethanol in newborn rats. The kappa opioid antagonist GNTI was as effective as nor-BNI. These effects of opioid antagonists on ethanol reinforcement are unlikely to be due to a disruption of all types of conditioning, since CTOP did not affect aversive reinforcement to intraoral infusions of quinine. The present results support the hypothesis that in newborn rats, the reinforcing properties of ethanol are mediated by the endogenous activity at mu and kappa opioid receptors.Los sistemas de opiáceos endógenos están implicados en los efectos reforzantes del alcohol y pueden desempeñar un papel sustancial en modular los efectos reforzantes centrales del etanol en la temprana ontogenia. El presente estudio indagó esta posibilidad a través de un paradigma de condicionamiento olfatorio en el que la administración central de etanol sirvió como estímulo incondicionado (EI). En el experimento 1, los neonatos de rata fueron pre-tratados con antagonistas selectivos para los receptores mu o kappa (CTOP y nor-BNI, respectivamente) y luego entrenados en condicionamiento olfatorio. El experimento 2 evaluó la capacidad de un antagonista kappa de corta duración (GNTI) en alterar la capacidad reforzante del etanol. El experimento 3 investigó si el bloqueo farmacológico de los receptores opiáceos podía causar una alteración inespecífica del condicionamiento olfatorio. Para ello se empleó como EI la administración intraoral de quinina. La administración central de los antagonistas opiáceos mu y kappa bloqueó los efectos reforzantes del etanol. La efectividad de GNTI fue similar a nor-BNI. Es poco probable que los efectos de antagonistas opiáceos sobre el reforzamiento al etanol sean explicados por una disrupción general de todos los tipos de condicionamiento; desde el momento en que CTOP no afecto el reforzamiento aversivo inducido por la infusión intraoral de quinina. Estos resultados respaldan la hipótesis de que las propiedades reforzantes del etanol en el neonato de rata están mediadas por la actividad endógena de los receptores opiáceos mu y kappa

Moderate Maternal Alcohol Exposure on Gestational Day 12 Impacts Anxiety-Like Behavior in Offspring

Among the numerous consequences of prenatal alcohol exposure (PAE) is an increase in anxiety-like behavior that can prove debilitating to daily functioning. A significant body of literature has linked gestational day 12 (G12) heavy ethanol exposure with social anxiety, evident in adolescent males and females. However, the association between non-social anxiety-like behavior and moderate alcohol exposure, a more common pattern of drinking in pregnant women, is yet unidentified. To model moderate PAE (mPAE), we exposed pregnant Sprague-Dawley rats to either room air or vaporized ethanol for 6 h on G12. Adolescent offspring were then tested on postnatal days (P) 41–47 in one of the following four anxiety assays: novelty-induced hypophagia (NIH), elevated plus maze (EPM), light-dark box (LDB) and open-field (OF). Our findings revealed significant increases in measures of anxiety-like behavior in male PAE offspring in the NIH, LDB and OF, with no differences observed in females on any test. Additionally, male offspring who demonstrated heightened anxiety-like behavior as adolescents demonstrated decreased anxiety-like behavior in adulthood, as measured by a marble-burying test (MBT), while females continued to be unaffected in adulthood. These results suggest that mPAE leads to dynamic changes in anxiety-like behavior exclusively in male offspring