Psychoneuroimmunology Meets Neuropsychopharmacology: Translational Implications of the Impact of Inflammation on Behavior

The potential contribution of chronic inflammation to the development of neuropsychiatric disorders such as major depression has received increasing attention. Elevated biomarkers of inflammation, including inflammatory cytokines and acute-phase proteins, have been found in depressed patients, and administration of inflammatory stimuli has been associated with the development of depressive symptoms. Data also have demonstrated that inflammatory cytokines can interact with multiple pathways known to be involved in the development of depression, including monoamine metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits relevant to mood regulation. Further understanding of mechanisms by which cytokines alter behavior have revealed a host of pharmacologic targets that may be unique to the impact of inflammation on behavior and may be especially relevant to the treatment and prevention of depression in patients with evidence of increased inflammation. Such targets include the inflammatory signaling pathways cyclooxygenase, p38 mitogen-activated protein kinase, and nuclear factor-κB, as well as the metabolic enzyme, indoleamine-2,3-dioxygenase, which breaks down tryptophan into kynurenine. Other targets include the cytokines themselves in addition to chemokines, which attract inflammatory cells from the periphery to the brain. Psychosocial stress, diet, obesity, a leaky gut, and an imbalance between regulatory and pro-inflammatory T cells also contribute to inflammation and may serve as a focus for preventative strategies relevant to both the development of depression and its recurrence. Taken together, identification of mechanisms by which cytokines influence behavior may reveal a panoply of personalized treatment options that target the unique contributions of the immune system to depression.     

Sex-Specific Effects of Cigarette Mentholation on Brain Nicotine Accumulation and Smoking Behavior

Menthol cigarettes are likely associated with greater risks of smoking dependence than non-menthol cigarettes. We sought to test the hypothesis that menthol increases the rate of brain nicotine accumulation (BNA) during smoking and thereby enhances its addictive effects. In a counter-balanced cross-over design, 10 menthol and 9 non-menthol smokers (10 females and 9 males; mean age 44.3) underwent two study phases. In each phase, the participant smoked exclusively either menthol or non-menthol research cigarettes for approximately 1 week prior to a positron emission tomography (PET) scan session, during which the subject''s head was scanned following inhalation of a single puff of smoke from a cigarette containing ¹¹C-nicotine. No differences in initial slope, C_max, area under curve (AUC), and T_1/2 of BNA were found between menthol and non-menthol cigarettes across all subjects; however, menthol relative to non-menthol cigarettes were associated with steeper initial slopes in men (p=0.008). Unexpectedly, women had faster BNA as indicated by greater values of the initial slope, C_max, AUC, and shorter T_1/2 than men (all ps<0.04). The rates of BNA were significantly correlated with ratings of smoking motivations of getting a ‘rush'', getting relaxing effects and marginally with alleviation of craving. These results do not provide strong support for the putative role of menthol in enhancing BNA, although further studies should explore the apparent effect of menthol on BNA in men. Fast BNA during smoking and preference of sensory properties of menthol cigarettes may independently or jointly contribute to smoking dependence among women.     

Independent and Combined Effects of Nicotine or Chronic Tobacco Smoking and HIV on the Brain: A Review of Preclinical and Clinical Studies

Tobacco smoking is highly prevalent among HIV-infected individuals. Chronic smokers with HIV showed greater cognitive deficits and impulsivity, and had more psychopathological symptoms and greater neuroinflammation than HIV non-smokers or smokers without HIV infection. However, preclinical studies that evaluated the combined effects of HIV-infection and tobacco smoking are scare. The preclinical models typically used cell cultures or animal models that involved specific HIV viral proteins or the administration of nicotine to rodents. These preclinical models consistently demonstrated that nicotine had neuroprotective and anti-inflammatory effects, leading to cognitive enhancement. Although the major addictive ingredient in tobacco smoking is nicotine, chronic smoking does not lead to improved cognitive function in humans. Therefore, preclinical studies designed to unravel the interactive effects of chronic tobacco smoking and HIV infection are needed. In this review, we summarized the preclinical studies that demonstrated the neuroprotective effects of nicotine, the neurotoxic effects of the HIV viral proteins, and the scant literature on nicotine or tobacco smoke in HIV transgenic rat models. We also reviewed the clinical studies that evaluated the neurotoxic effects of tobacco smoking, HIV infection and their combined effects on the brain, including studies that evaluated the cognitive and behavioral assessments, as well as neuroimaging measures. Lastly, we compared the different approaches between preclinical and clinical studies, identified some gaps and proposed some future directions.

Independent and combined effects of HIV and tobacco/nicotine. Left top and bottom panels: Both clinical studies of HIV infected persons and preclinical studies using viral proteins in vitro or in vivo in animal models showed that HIV infection could lead to neurotoxicity and neuroinflammation. Right top and bottom panels: While clinical studies of tobacco smoking consistently showed deleterious effects of smoking, clinical and preclinical studies that used nicotine show mild cognitive enhancement, neuroprotective and possibly anti-inflammatory effects. In the developing brain, however, nicotine is neurotoxic. Middle overlapping panels: Clinical studies of persons with HIV who were smokers typically showed additive deleterious effects of HIV and tobacco smoking. However, in the preclinical studies, when nicotine was administered to the HIV-1 Tg rats, the neurotoxic effects of HIV were attenuated, but tobacco smoke worsened the inflammatory cascade.

     

Novel Use of a Lipid-Lowering Fibrate Medication to Prevent Nicotine Reward and Relapse: Preclinical Findings

Experimental drugs that activate α-type peroxisome proliferator-activated receptors (PPARα) have recently been shown to reduce the rewarding effects of nicotine in animals, but these drugs have not been approved for human use. The fibrates are a class of PPARα-activating medications that are widely prescribed to improve lipid profiles and prevent cardiovascular disease, but these drugs have not been tested in animal models of nicotine reward. Here, we examine the effects of clofibrate, a representative of the fibrate class, on reward-related behavioral, electrophysiological, and neurochemical effects of nicotine in rats and squirrel monkeys. Clofibrate prevented the acquisition of nicotine-taking behavior in naive animals, substantially decreased nicotine taking in experienced animals, and counteracted the relapse-inducing effects of re-exposure to nicotine or nicotine-associated cues after a period of abstinence. In the central nervous system, clofibrate blocked nicotine''s effects on neuronal firing in the ventral tegmental area and on dopamine release in the nucleus accumbens shell. All of these results suggest that fibrate medications might promote smoking cessation. The fact that fibrates are already approved for human use could expedite clinical trials and subsequent implementation of fibrates as a treatment for tobacco dependence, especially in smokers with abnormal lipid profiles.     

Tissue Physiology of Cynomolgus Monkeys: Cross-Species Comparison and Implications for Translational Pharmacology

We previously performed a comparative assessment of tissue-level vascular physiological parameters in mice and rats, two of the most commonly utilized species in translational drug development. The present work extends this effort to non-human primates by measuring tissue- and organ-level vascular volumes (V_v), interstitial volumes (V_i), and blood flow rates (Q) in cynomolgus monkeys. These measurements were accomplished by red blood cell labeling, extracellular marker infusion, and rubidium chloride bolus distribution, respectively, the same methods used in previous rodent measurements. In addition, whole-body blood volumes (BV) were determined across species. The results demonstrate that V_v, V_i, and Q, measured using our methods scale approximately by body weight across mouse, rat, and monkey in the tissues considered here, where allometric analysis allowed extrapolation to human parameters. Significant differences were observed between the values determined in this study and those reported in the literature, including V_v in muscle, brain, and skin and Q in muscle, adipose, heart, thymus, and spleen. The impact of these differences for selected tissues was evaluated via sensitivity analysis using a physiologically based pharmacokinetic model. The blood-brain barrier in monkeys was shown to be more impervious to an infused radioactive tracer, indium-111-pentetate, than in mice or rats. The body weight-normalized total BV measured in monkey agreed well with previously measured value in rats but was lower than that in mice. These findings have important implications for the common practice of scaling physiological parameters from rodents to primates in translational pharmacology.     

Nicotine modulation of fear memories and anxiety: Implications for learning and anxiety disorders

Anxiety disorders are a group of crippling mental diseases affecting millions of Americans with a 30% lifetime prevalence and costs associated with healthcare of $42.3 billion. While anxiety disorders show high levels of co-morbidity with smoking (45.3% vs. 22.5% in healthy individuals), they are also more common among the smoking population (22% vs. 11.1% in the non-smoking population). Moreover, there is clear evidence that smoking modulates symptom severity in patients with anxiety disorders. In order to better understand this relationship, several animal paradigms are used to model several key symptoms of anxiety disorders; these include fear conditioning and measures of anxiety. Studies clearly demonstrate that nicotine mediates acquisition and extinction of fear as well as anxiety through the modulation of specific subtypes of nicotinic acetylcholine receptors (nAChRs) in brain regions involved in emotion processing such as the hippocampus. However, the direction of nicotine’s effects on these behaviors is determined by several factors that include the length of administration, hippocampus-dependency of the fear learning task, and source of anxiety (novelty-driven vs. social anxiety). Overall, the studies reviewed here suggest that nicotine alters behaviors related to fear and anxiety and that nicotine contributes to the development, maintenance, and reoccurrence of anxiety disorders.     

The Effects of Food on Mood and Behavior: Implications for the Addictions Model of Obesity and Eating Disorders

SUMMARY

The addictions model of obesity claims that individuals gain excess weight due to their dependence on and inability to control the intake of certain food substances. The dependence and lack of control over these food substances is undergirded by, according to the addictions model, the psychoactive properties of foods. The article reviews the literature on the purported psychoactive effects of foods and concludes that although, under certain circumstances, some food substances may have subtle effects on mood and behavior, the effects of food are quite different from that of psychoactive drugs such as nicotine and alcohol. Therefore, the food addictions model is unlikely to provide a fruitful paradigm for understanding the complex problem of obesity.     

Effects of Nicotine During Pregnancy: Human and Experimental Evidence

Prenatal exposure to tobacco smoke is a major risk factor for the newborn, increasing morbidity and even mortality in the neonatal period but also beyond. As nicotine addiction is the factor preventing many women from smoking cessation during pregnancy, nicotine replacement therapy (NRT) has been suggested as a better alternative for the fetus. However, the safety of NRT has not been well documented, and animal studies have in fact pointed to nicotine per se as being responsible for a multitude of these detrimental effects. Nicotine interacts with endogenous acetylcholine receptors in the brain and lung, and exposure during development interferes with normal neurotransmitter function, thus evoking neurodevelopmental abnormalities by disrupting the timing of neurotrophic actions. As exposure to pure nicotine is quite uncommon in pregnant women, very little human data exist aside from the vast literature on prenatal exposure to tobacco smoke.     

Effects of Chronic Varenicline Treatment on Nicotine,Cocaine, and Concurrent Nicotine+Cocaine Self-Administration

Nicotine dependence and cocaine abuse are major public health problems, and most cocaine abusers also smoke cigarettes. An ideal treatment medication would reduce both cigarette smoking and cocaine abuse. Varenicline is a clinically available, partial agonist at α4β2* and α6β2* nicotinic acetylcholine receptors (nAChRs) and a full agonist at α7 nAChRs. Varenicline facilitates smoking cessation in clinical studies and reduced nicotine self-administration, and substituted for the nicotine-discriminative stimulus in preclinical studies. The present study examined the effects of chronic varenicline treatment on self-administration of IV nicotine, IV cocaine, IV nicotine+cocaine combinations, and concurrent food-maintained responding by five cocaine- and nicotine-experienced adult rhesus monkeys (Macaca mulatta). Varenicline (0.004–0.04 mg/kg/h) was administered intravenously every 20 min for 23 h each day for 7–10 consecutive days. Each varenicline treatment was followed by saline-control treatment until food- and drug-maintained responding returned to baseline. During control treatment, nicotine+cocaine combinations maintained significantly higher levels of drug self-administration than nicotine or cocaine alone (P<0.05–0.001). Varenicline dose-dependently reduced responding maintained by nicotine alone (0.0032 mg/kg/inj) (P<0.05), and in combination with cocaine (0.0032 mg/kg/inj) (P<0.05) with no significant effects on food-maintained responding. However, varenicline did not significantly decrease self-administration of a low dose of nicotine (0.001 mg/kg), cocaine alone (0.0032 and 0.01 mg/kg/inj), or 0.01 mg/kg cocaine combined with the same doses of nicotine. We conclude that varenicline selectively attenuates the reinforcing effects of nicotine alone but not cocaine alone, and its effects on nicotine+cocaine combinations are dependent on the dose of cocaine.     

虫草素对人胃癌细胞系HGC-27的影响及分子机制

目的 探讨虫草素对HGC-27细胞增殖、运动性和凋亡的影响及相关机制。方法 用不同浓度虫草素处理人胃癌细胞系HGC-27、AGS和MGC-803,利用CCK-8法检测细胞活力,集落形成试验检测细胞增殖能力,流式细胞术检测细胞凋亡情况,体外划痕试验检测细胞运动性。Western blot检测Bcl-2、Bax、ERK、磷酸化ERK（p-ERK）和糖原合成酶激酶-3β（GSK-3β）蛋白表达水平。结果 与对照组相比,虫草素处理组明显抑制细胞增殖、集落形成率、细胞运动性并诱导细胞凋亡,下调Bcl-2、GSK-3β和p-ERK蛋白表达水平,且呈浓度和时间依赖性,但对Bax蛋白表达水平没有影响。结论 虫草素通过调节ERK/GSK-3β信号通路起到抗肿瘤作用,有望成为临床干预和治疗胃癌的潜在药物。     

Prenatal Exposure to Nicotine: Effects on Prepulse Inhibition and Central Nicotinic Receptors

The present experiment examined effects of prenatal nicotine exposure (6 mg/kg/day via osmotic minipump) throughout gestation on prepulse inhibition of the acoustic startle response (PPI) and on the density of nicotinic acetylcholine receptors (nAchRs) in the brains of 5-week-old Sprague–Dawley rats. A total of 117 male and 103 female offspring were used. Prenatal nicotine reduced subsequent percent PPI to a 98 dB stimulus in female but not in male offspring. There was an inverse correlation between the percent of PPI and nAchR density in the cortex of male rats and the striatum of female rats.     

Aldehyde Sources,Metabolism, Molecular Toxicity Mechanisms,and Possible Effects on Human Health

Aldehydes are organic compounds that are widespread in nature. They can be formed endogenously by lipid peroxidation (LPO), carbohydrate or metabolism ascorbate autoxidation, amine oxidases, cytochrome P-450s, or myeloperoxidase-catalyzed metabolic activation. This review compares the reactivity of many aldehydes towards biomolecules particularly macromolecules. Furthermore, it includes not only aldehydes of environmental or occupational concerns but also dietary aldehydes and aldehydes formed endogenously by intermediary metabolism. Drugs that are aldehydes or form reactive aldehyde metabolites that cause side-effect toxicity are also included. The effects of these aldehydes on biological function, their contribution to human diseases, and the role of nucleic acid and protein carbonylation/oxidation in mutagenicity and cytotoxicity mechanisms, respectively, as well as carbonyl signal transduction and gene expression, are reviewed. Aldehyde metabolic activation and detoxication by metabolizing enzymes are also reviewed, as well as the toxicological and anticancer therapeutic effects of metabolizing enzyme inhibitors. The human health risks from clinical and animal research studies are reviewed, including aldehydes as haptens in allergenic hypersensitivity diseases, respiratory allergies, and idiosyncratic drug toxicity; the potential carcinogenic risks of the carbonyl body burden; and the toxic effects of aldehydes in liver disease, embryo toxicity/teratogenicity, diabetes/hypertension, sclerosing peritonitis, cerebral ischemia/neurodegenerative diseases, and other aging-associated diseases.     

Reward Sensitization: Effects of Repeated Nicotine Exposure and Withdrawal in Mice

Tobacco dependence is an addiction with high rates of relapse, resulting in multiple quit attempts in individuals who are trying to stop smoking. How these multiple cycles of smoking and withdrawal contribute to nicotine dependence, long-term alterations in brain reward systems, and nicotine receptor regulation is unknown. Therefore, to evaluate how multiple exposures of nicotine and withdrawal periods modulate rewarding properties of nicotine, we used intracranial self-stimulation to measure alterations in the threshold of brain stimulation reward. In addition, we employed the conditioned place preference (CPP) paradigm to evaluate positive context conditioning following each withdrawal period and measured levels of neuronal nicotinic receptors in cortex, striatum, and hippocampus. We found that repeated nicotine exposure and withdrawal enhanced brain stimulation reward and reward sensitivity to acute injections of nicotine. This increased reward was reflected by enhanced CPP to nicotine. Chronic nicotine is known to up-regulate nAChRs (nicotinic acetylcholine receptors) and we found that this up-regulation was maintained for up to 8 days of withdrawal in the striatum and in the hippocampus, but not in the cortex, of animals exposed to multiple nicotine exposure and withdrawal periods. These results demonstrate that repeated exposures to nicotine, followed by withdrawal, induce a persistent increase in both brain reward function and sensitivity to the hedonic value of nicotine and long-lasting up-regulation of neuronal nicotinic receptors. Together, these data suggest that a continuing increase in brain reward function and enhanced sensitivity to nicotine reward following repeated withdrawal periods may be one reason why smokers relapse frequently.     

Neuronal Responses to Systemic Nicotine in the Solitary Tract Nucleus: Origin and Possible Relation with Nutritional Effects of Nicotine

Single-unit activity was recorded extracellularly in the caudal part of the solitary tract nucleus of anesthetized rats. Of 60 recorded neurons, 44 (73.3%) responded to intravenous (IV) nicotine. The incidence of response was significantly greater in the cells sensitive to moderate changes in blood glucose level, suggesting that the effects of nicotine on food intake and body weight are partly mediated by the glycemia-sensitive neurons in the caudal nucleus tractus solitarius. Only one-fourth of the neurons affected by IV nicotine responded in the same direction to iontophoretic nicotine application, suggesting that sensitivity to systemic nicotine results mainly from an indirect mechanism. Based on the observed effects of nicotinic agonists and antagonists unable to cross the blood–brain barrier, a majority of indirect unit responses to IV nicotine might be mediated by peripheral receptors, while the remaining ones might involve central or both central and peripheral receptors.