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
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引用次数: 0
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.
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.