A novel alcohol+nicotine co-use self-administration procedure reveals sex differences and differential alteration of mesocorticolimbic TLR- and cholinergic-related neuroimmune gene expression in rats

IF 2.5 4区 医学 Q3 PHARMACOLOGY & PHARMACY Alcohol Pub Date : 2024-08-27 DOI:10.1016/j.alcohol.2024.08.003
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Abstract

Although alcohol and nicotine are two of the most commonly co-used drugs with upwards of 90% of adults with an alcohol use disorder (AUD) in the US also smoking, we don't tend to study alcohol and nicotine use this way. The current studies sought to develop and assess a novel alcohol + nicotine co-access self-administration (SA) model in adult male and female Long-Evans rats. Further, both drugs are implicated in neuroimmune function, albeit in largely opposing ways. Chronic alcohol use increases neuroinflammation via toll-like receptors (TLRs) which in turn increases alcohol intake. By contrast, nicotine produces anti-inflammatory effects, in part, through the monomeric alpha7 receptor (ChRNa7). Following long-term co-access (6 months), rats reliably administered both drugs during daily sessions, however males generally responded for more alcohol and females for nicotine. This was reflected in plasma analysis with translationally relevant intake levels of both alcohol and nicotine, making it invaluable in studying the effects of co-use on behavior and CNS function. Moreover, male rats show sensitivity to alterations in alcohol concentration whereas females show sensitivity to alterations in nicotine concentration. Rats trained on this procedure also developed an anxiogenic phenotype. Finally, we assessed alterations in neuroimmune-related gene expression in the medial prefrontal cortex – prelimbic, (mPFC-PL), nucleus accumbens core (AcbC), and ventral tegmental area (VTA). In the AcbC, where α7 expression was increased and β2 was decreased, markers of pro-inflammatory activity were decreased, despite increases in TLR gene expression suggesting that co-use with nicotine modulates inflammatory state downstream from the receptor level. By contrast, in mPFC-PL where α7 was not increased, both TLRs and downstream proinflammatory markers were increased. Taken together, these findings support that there are brain regional and sex differences with co-use of alcohol + nicotine SA and suggest that targeting nicotinic α7 may represent a novel strategy for treating alcohol + nicotine co-dependence.

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一种新型的酒精+尼古丁共用自我给药程序揭示了大鼠的性别差异以及间皮质边缘TLR和胆碱能相关神经免疫基因表达的不同改变。
虽然酒精和尼古丁是两种最常见的共同使用药物,在美国,90%以上患有酒精使用障碍(AUD)的成年人同时也吸烟,但我们并不倾向于以这种方式研究酒精和尼古丁的使用。目前的研究试图在成年雄性和雌性 Long-Evans 大鼠中开发和评估一种新型的酒精和尼古丁共同获取自我给药模型(SA)。此外,这两种药物都与神经免疫功能有关,尽管它们的作用方式基本相反。长期饮酒会通过类收费受体(TLRs)增加神经炎症,进而增加酒精摄入量。相比之下,尼古丁则部分通过单体α7受体(ChRNa7)产生抗炎作用。在长期共同摄入(6 个月)后,大鼠在每天的训练中都能可靠地服用这两种药物,但雄性大鼠通常对酒精的反应更多,而雌性大鼠则对尼古丁的反应更多。这反映在血浆分析中,酒精和尼古丁的摄入量都与转化相关,因此在研究共同使用对行为和中枢神经系统功能的影响方面非常有价值。此外,雄性大鼠对酒精浓度的变化表现出敏感性,而雌性大鼠则对尼古丁浓度的变化表现出敏感性。接受过这种训练的大鼠也会产生焦虑表型。最后,我们评估了内侧前额叶皮层-边缘前区(mPFC-PL)、伏隔核核心(AcbC)和腹侧被盖区(VTA)中神经免疫相关基因表达的变化。在AcbC,α7的表达增加,β2的表达减少,尽管TLR基因表达增加,但促炎活动的标记物却减少了,这表明与尼古丁共同使用会从受体水平下游调节炎症状态。相比之下,在 mPFC-PL 中,α7 没有增加,但 TLR 和下游促炎标记物都增加了。综上所述,这些研究结果表明,在同时使用酒精和尼古丁的情况下,大脑存在区域和性别差异,并表明以尼古丁α7为靶点可能是治疗酒精和尼古丁共同依赖的一种新策略。
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来源期刊
Alcohol
Alcohol 医学-毒理学
CiteScore
4.60
自引率
4.30%
发文量
74
审稿时长
15.6 weeks
期刊介绍: Alcohol is an international, peer-reviewed journal that is devoted to publishing multi-disciplinary biomedical research on all aspects of the actions or effects of alcohol on the nervous system or on other organ systems. Emphasis is given to studies into the causes and consequences of alcohol abuse and alcoholism, and biomedical aspects of diagnosis, etiology, treatment or prevention of alcohol-related health effects. Intended for both research scientists and practicing clinicians, the journal publishes original research on the neurobiological, neurobehavioral, and pathophysiological processes associated with alcohol drinking, alcohol abuse, alcohol-seeking behavior, tolerance, dependence, withdrawal, protracted abstinence, and relapse. In addition, the journal reports studies on the effects alcohol on brain mechanisms of neuroplasticity over the life span, biological factors associated with adolescent alcohol abuse, pharmacotherapeutic strategies in the treatment of alcoholism, biological and biochemical markers of alcohol abuse and alcoholism, pathological effects of uncontrolled drinking, biomedical and molecular factors in the effects on liver, immune system, and other organ systems, and biomedical aspects of fetal alcohol spectrum disorder including mechanisms of damage, diagnosis and early detection, treatment, and prevention. Articles are published from all levels of biomedical inquiry, including the following: molecular and cellular studies of alcohol''s actions in vitro and in vivo; animal model studies of genetic, pharmacological, behavioral, developmental or pathophysiological aspects of alcohol; human studies of genetic, behavioral, cognitive, neuroimaging, or pathological aspects of alcohol drinking; clinical studies of diagnosis (including dual diagnosis), treatment, prevention, and epidemiology. The journal will publish 9 issues per year; the accepted abbreviation for Alcohol for bibliographic citation is Alcohol.
期刊最新文献
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