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عنوان فارسی:
اثر متقابل اتانول و نیکوتین در موش های صحرایی نر و ماده نوجوان: بررسی اثرات پاداش دهنده آنها به عنوان تابعی از دوز

عنوان انگلیسی:

The Interaction of Ethanol and Nicotine in Male and Female Adolescent Rats: Examination of Their Rewarding Effects as a Function of Dose

Abstract

Ethanol and nicotine are two of the most commonly abused recreational substances, and adolescence is the most common stage of life to initiate their use. Currently, there is little preclinical research investigating the effects of coadministration of ethanol and nicotine in adolescence. While the rewarding effects of nicotine are well-established in adolescent rats, the data on ethanol reward is not as well-established. The most common and validated animal model to examine drug reward is the conditioned place preference (CPP) paradigm. Thus, the purpose of this study is twofold. First, we conducted an experiment to establish ethanol preferences in adolescent male and female rats using the CPP paradigm. Second, we then investigated the rewarding effects of ethanol and/or nicotine in male and female rats using the CPP paradigm. The CPP procedure took place over 10 days and consisted of three phases: preconditioning, conditioning, and postconditioning. During preconditioning, the rats had free access to both sides of the CPP box so that an initial side-preference could be established. After preconditioning, the rats underwent an 8-day conditioning period, consisting of four 2-day cycles. On day one, rats are administered ethanol and/or nicotine and then confined to their initially non-preferred side. The next day rats are administered saline and confined to their initially preferred side. A biased CPP design was used, meaning the drug was paired with the rats’ initially non-preferred side throughout conditioning to make shifts in preference easier to detect. During postconditioning, rats were again allowed free access to both sides of the CPP box to reevaluate their preference. In Experiment 1, ethanol-induced CPP depended on the pattern and quantity of ethanol dosing; however, unlike our hypothesis, the fixed pattern of ethanol produced more robust CPP preferences than the ascending pattern. Using the fixed pattern of ethanol dosing from Experiment 1, the coadministration of the two drugs did not produce strong preferences in Experiment 2, although there was some indication of an interaction. These experiments have added to the literature concerning ascending versus fixed dosing in CPP and the understanding of how ethanol and nicotine interact in adolescent male and female rats. Future experiments are needed to uncover potential brain mechanisms involved.

عنوان فارسی:
قرار گرفتن متوالی در معرض منگنز و عفونت ویروسی انسفالیتیک باعث بروز یک فنوتیپ پارکینسونی می شود که احتمالاً با واسطه آستروگلیوز است.

عنوان انگلیسی:

Sequential Exposure to Manganese and Encephalitic Viral Infection Causes a Parkinsonian Phenotype Likely Mediated by Astrogliosis

Abstract

Developmental exposure to environmental toxins increases neuronal susceptibility to injury from subsequent viral challenges. Neurodegenerative diseases such as Parkinson’s Disease (PD) present with a neuroinflammatory component often linked to environmental risk factors— including toxic metals, chemicals, physical injury, and viral infection. While many of these risk factors are sufficient to cause a Parkinsonian disease state, none have been shown to be necessary, suggesting an underlying shared mechanism. Furthermore, for any individual risk factor, there is high variability regarding development and severity of the disease. One way to address these issues employs multiple risk factors to model the disease more accurately, although it is unclear how or why multiple unrelated insults have a compounding effect. Neuroinflammation is a shared consequence of the known environmental risk factors. Increased susceptibility to one insult following a challenge with another environmental toxicant may therefore be mediated by neuroinflammatory signaling cascades, a process largely regulated by glial cells, primarily astrocytes. Reactive astrocytes produce neuroinflammatory cytokines, the expression of which is governed by the transcription factor complex NF-κB, and its regulatory kinase, IKK2. The current study uses a two-hit model of environmental neurodegeneration, juvenile exposure to manganese (Mn) followed by adult infection with western equine encephalitic virus (WEEV). We found that WEEV alone produced a significant PD effect, evident by immunohistological staining of pathogenic markers and behavioral analyses; and that WEEV and Mn exposure partially enhanced this effect. These exposures were conducted in both wildtype mice and in astrocyte-specific knockout mice lacking nuclear factor Ikappa-B kinase subunit beta (IKK-KO), hypothesizing that innate immune inflammatory signaling in reactive astrocytes modulates neuroinflammation and neuronal injury following combined exposure to Mn and WEEV. In multi-hit and single exposure treatment groups, IKK-KO mice displayed reduced viral replication and had decreased α-synuclein protein aggregation, astrogliosis and neuronal loss in multiple brain regions including the substantia nigra pars compacta, suggesting that astrocyte-mediated neuroinflammation may be one mechanism by which developmental toxin exposure can potentiate vulnerability to subsequent viral infections. Given the relevance of metal toxicity and viral infection to public health, these results provide insight into disease etiology and support further exploration of neuroinflammation as a mechanism of neurodegenerative pathologies.