Effects Of Nicotine Research Articles

Nicotine-mediated dopamine regulates short neuropeptide F to inhibit brown planthopper feeding behavior in tobacco-rice rotation cropping.

The tobacco-rice rotation cropping (TRRC) is an ecologically friendly system that can both alleviate soil nicotine pollution and decrease the brown planthopper (BPH, Nilaparvata lugens Stål) fitness on rice. However, few studies on this green and effective rotational cropping system have been reported. In particular, the underlying mechanisms of TRRC on the significant reduction of field pest population at the molecular level is still unknown. Field investigation showed that BPH population decreased significantly in TRRC than in rice-rice successive cropping (RRSC) field. In addition, the short neuropeptide F (NlsNPF) and its receptor NlA7 of BPH had half-times lower levels in the TRRC field. Behavioral bioassay indicated a 1.93-fold increase in the number of salivary flanges of the dsNlsNPF group, while BPH fitness parameters, such as honeydew, weight gain, and mortality decreased significantly. Dopamine (DA) content in BPH decreased by ~11.1% under the influence of nicotine, and its presence increased the expression levels of NlsNPF and NlA7. Exogenous DA application eliminated the inhibitory effects of nicotine on BPH feeding and restored the fitness levels of its parameters. Independent application of either a mixture of dsNlsNPF with a nanocarrier or nicotine to the normal rice field revealed that the latter could produce better effects in combination with dsRNA. These findings confirmed that DA regulated NlsNPF to inhibit the BPH feeding behavior in TRRC. The results not only provided novel findings on the mechanism of pest-host interactions, but also presented new method for integrated pest management. © 2023 Society of Chemical Industry.

Nicotine destructs dental stem cell-based periodontal tissue regeneration

Background/purposeNicotine is a widely known addictive and toxic substance in cigarette that exacerbates periodontitis. However, its deleterious effects on dental stem cells and subsequent implications in tissue regeneration remain unclear. This study aimed to explore the effects of nicotine on the regenerative capacity of human periodontal ligament stem cells (hPDLSCs) based on transcriptomics and proteomics, and determined possible targeted genes associated with smoking-related periodontitis. Materials and methodshPDLSCs were treated with different concentrations of nicotine ranging from 10−3 to 10−8 M. Transcriptomics and proteomics were performed and confirmed employing Western blot, 5-ethynyl-2′-deoxyuridine (EdU), and alkaline phosphatase (ALP) staining. A ligature-induced periodontitis mouse model was established and administrated with nicotine (16.2 μg/10 μL) via gingival sulcus. The bone resorption was assessed by micro-computed tomography and histological staining. Key genes were identified using multi-omics analysis with verifications in hPDLSCs and human periodontal tissues. ResultsBased on enrichments analysis, nicotine-treated hPDLSCs exhibited decreased proliferation and differentiation abilities. Local administration of nicotine in mouse model significantly aggravated bone resorption and undermined periodontal tissue regeneration by inhibiting the endogenous dental stem cells regenerative ability. HMGCS1, GPNMB, and CHRNA7 were hub-genes according to the network analysis and corelated with proliferation and differentiation capabilities, which were also verified in both cells and tissues. ConclusionOur study investigated the destructive effects of nicotine on the regeneration of periodontal tissues from aspects of in vitro and in vivo with the supporting information from both transcriptome and proteome, providing novel targets into the molecular mechanisms of smoking-related periodontitis.

Cardiovascular dysfunction induced by combined exposure to nicotine inhalation and high fat diet

Cardiovascular diseases (CVD) are the leading cause of death worldwide, and smoking remains the most significant preventable risk factor. The contribution of nicotine, the addictive component of all tobacco products, to smoking-related CVD remains poorly understood. In addition to smoking, obesity is also a major risk factor for the development of CVD. Recent studies indicate that individuals who are overweight or obese are at greater risk of nicotine product usage. With more than 40% of the US population affected by obesity, the combined effects of obesity and nicotine on cardiovascular (CV) health warrant urgent investigation. In the present study we investigated the combined effects of nicotine exposure and a high fat diet (HFD) on CV function.Male C57BL/6N mice (8 wk-old) were placed on either a HFD (60 kcal% Fat) or standard chow (SC, 22 kcal% Fat) and exposed to room air (RA) or nicotine vapor (NIC, 12 hr/day during the active phase) for 10 weeks (n=10-15/group). Mice with HFD exposure alone exhibited significantly greater weight gain at 10 weeks vs. SC-RA controls (122.5±9.8% increase in body weight in HFD-RA vs. 40.7±3.3% in SC-RA, p < 0.0001), whereas concurrent nicotine inhalation significantly reduced this weight gain (66.5±5.8% in HFD-NIC group, p < 0.0001). In the HFD-NIC group, blood pressure (BP) monitoring via telemetry (24 hours) revealed non-significant increases in BP in the inactive phase, coupled with a significant (p < 0.05) reduction in the expected dipping in BP during the inactive compared to the active phase (HFD-NIC: 4.5±1.2; SC-RA: 11.3±2.2; HFD-RA: 12.4±1.0 and SC-NIC: 9.7±4.6 mmHg). LV catheterization showed that mice exposed to both nicotine and HFD had elevated LV end diastolic pressure (HFD-NIC: 14.1±0.7; SC-RA: 4.5±0.8; HFD-RA: 2.8±0.7 and SC-NIC: 3.9±1.3 mmHg; p<0.05) and prolonged time constant of LV relaxation (Tau). LV RNAseq analysis revealed that HFD-NIC resulted in 70 differentially expressed genes (36 upregulated and 34 downregulated) unique from nicotine or HFD alone, with multiple differentially regulated pathways including dilated cardiomyopathy signaling pathway (p = 2.8E-04). Plasma NT-pro-BNP levels were significantly increased in HFD-RA mice vs. SC-RA controls, whereas this response was absent in HFD-NIC. Finally, HFD+NIC led to greater impairment of endothelium-dependent vasorelaxation in thoracic aortas compared to either treatment alone.In conclusion, although nicotine reduced HFD-induced weight gain, combined exposure to inhaled nicotine and HFD led to greater cardiovascular dysfunction including dysregulation in physiological blood pressure responses, LV diastolic dysfunction, and greater impairment of endothelial-dependent vascular function. National Institute of Health [grant numbers HL135635 (to JDG, EL and XY); HL146098, HL146514, and HL151398 (to DJL.); and F30HL160071 (to AKW)]; Department of Veterans Affairs (BX004294 to EL) and the American Heart Association [Award 829761 (to AKW) and Award 20POST35200075 (to ZL)]. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Co-exposure to cannabis and nicotine during pregnancy alters fetal lung development

Rationale: The co-use of cigarettes and cannabis is increasing especially in regions where recreational marijuana use has become legal. However, the use of these dependent substances during pregnancy poses a serious risk on fetal development and health (low birth weight, preterm birth, and perinatal death). Nevertheless, the impact of co-exposure to the most prominent cannabinoids found in Cannabis sativa (Trans-Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD)) with nicotine on fetal lung development is not well understood. This study aims to determine the effect of nicotine, CBD, and THC, alone or combined, on human lung development through investigating cellular senescence. Methods: In vitro human fetal lung explants from 10–20 weeks gestation were cultured on air-liquid interface and treated with physiological concentrations of CBD, THC, and nicotine, alone or combined, for 72h. Similarly, lung mesenchymal cells (LMCs) were isolated from the same samples and treated for 48h. Both culture types were either fixed for immunofluorescent staining or used for RNA extraction and qRT-PCR. Results: Our results showed that nicotine and CBD induce thickening of the mesenchymal compartment of lung explants. Furthermore, treatment with either CBD or THC, or the two combined, induced an increase in epithelial cysting. Ki-67 staining demonstrated increased proliferation following treatment with nicotine, THC and CBD+THC+nicotine. ACTA2 staining, a marker for smooth muscle cells, decreased following treatment with THC, CBD, and nicotine as well as all 3 combined, while the senescence marker p21 increased following exposure to nicotine, CBD+THC, as well as CBD+THC+nicotine. qRT-PCR data showed decreased expression of ACTA2 in the presence of CBD, THC, CBD+THC, and CBD+THC+nicotine, and increased expression of CDKN1A (encoding p21) and CDKN2A (encoding p16) in response to CBD+THC+nicotine. LMCs treated with nicotine, CBD, and THC demonstrated an increase in cell proliferation and senescence as shown by Ki-67 and p21 staining respectively, and a decrease in ACTA2. These data were confirmed by qRT-PCR that showed a decrease in ACTA2 for the LMCs treated with either nicotine or CBD+THC+nicotine and an increase in senescence genes CDKN1A and CDKN2A. Moreover, the expression of these genes was higher in the LMCs derived from second trimester samples in comparison to those of the first trimester. Conclusion: Our results showed that the co-exposure to nicotine and cannabis induces senescence and alters lung fetal cellular proliferation, especially when used in conjunction. Furthermore, this effect appears to be age dependent. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Nicotine Dependence and Perceived Stress during the Pandemic

Background The development of COVID-19, which continues to increase in Indonesia, impacts the Indonesian people and causes stress due to the impact of the COVID-19 pandemic. Prior studies in several countries have shown that stress affects smokers during the COVID-19 pandemic. It affects smokers in two different ways, either they increase smoking or decrease smoking. This study aimed to determine the effect of Nicotine, smoking history, and changes in smoking habits during the COVID-19 pandemic on stress in smokers. Methods We conducted an online survey among active smokers in one of the villages in the South Lampung district, Indonesia November 2020 (n = 150). The survey includes sex, marital status, age of smoking initiation, duration as a smoker, changes in smoking frequency, questionnaire for nicotine dependence (the Fagerstrom Test for Nicotine Dependence questionnaire) and The Perceived Stress Scale (PSS). Data were analyzed with Chi-square<0.05). Results The results showed that the PSS score had a significant association with changes in smoking frequency (p=0.004) and nicotine dependence (p=0.001). Conclusions The study concluded that variations in nicotine dependence and changing smoking habits impacted perceived stress in smokers during the pandemic. There is a significant relationship between age at starting to smoke, number of cigarettes per day, duration of smoking habits, degree of smoking habits, and changes in smoking habits with stress levels in smokers in the COVID-19 pandemic era, and there is no relationship between types of cigarettes consumed, and stress levels in smokers in COVID-19 pandemic era.

The association between risk perceptions, anxiety, and self-reported changes in tobacco and nicotine product use due to COVID-19 in May-June 2020 in Israel

BackgroundEarly in the COVID-19 pandemic, reports about a possible protective effect of nicotine on COVID-19 conflicted with messaging by public health organizations about increased risks of COVID-19 due to smoking. The ambiguous information the public received, combined with COVID-19-induced anxiety, may have led to changes in tobacco or other nicotine product use. This study examined changes in use of combustible cigarettes (CCs), nargila (hookah/waterpipe), e-cigarettes, and IQOS and home-smoking behaviors. We also assessed COVID-19 related anxiety and perceptions regarding changes in risk of COVID-19 severity due to smoking.MethodsWe used cross-sectional data from a population telephone survey that was conducted in Israel in the early phase of the COVID-19 pandemic (May–June 2020) and included 420 adult (age 18+) individuals who reported having ever used CCs (n = 391), nargila (n = 193), and/or electronic cigarettes (e-cigarettes)/heated tobacco products (e.g., IQOS) (n = 52). Respondents were asked about the effect that COVID-19 had on their nicotine product use (quit/reduced use, no change, increased use). We assessed changes in product use, risk perceptions, and anxiety using adjusted multinomial logistic regression analyses.ResultsMost respondents did not change their frequency of product use (CCs: 81.0%, nargila: 88.2%, e-cigarettes/IQOS: 96.8%). A small percentage either decreased use (CCs: 7.2%, nargila: 3.2%, e-cigarettes/IQOS:2.4%) or increased use (CCs:11.8%, nargila:8.6%, e-cigarettes/IQOS:+ 0.9%). 55.6% of respondents used a product in the home prior to COVID-19; but during the first lockdown COVID-19 period, a greater percentage increased (12.6%) than decreased (4.0%) their home use. Higher levels of anxiety due to COVID-19 were associated with increased home smoking (aOR = 1.59, 95% CI:1.04–2.42, p = 0.02). Many respondents believed that increased severity of COVID-19 illness was associated with CCs (62.0%) and e-cigarettes/vaping (45.3%), with uncertainty about the association being lower for CCs (20.5%) than for vaping (41.3%).ConclusionsWhile many respondents believed that nicotine product use (particularly CCs and e-cigarettes) was associated with increased risk of COVID-19 disease severity, the majority of users did not change their tobacco/nicotine use. The confusion about the relationship between tobacco use and COVID-19 calls for clear evidence-based messaging from governments. The association between home smoking and increased COVID-19-related stress suggests the need for campaigns and resources to prevent smoking in the home, particularly during times of stress.

Double dissociation of perirhinal nicotinic acetylcholine receptors and dopamine D2 receptors in modulation of object memory consolidation by nicotine, cocaine and their conditioned stimuli

There are indications that drug conditioned stimuli (CS) may activate neurochemical systems of memory modulation that are activated by the drugs themselves. To directly test this hypothesis, a cholinergic nicotinic receptor antagonist (mecamylamine; MEC: 0, 10 or 30 µg/side) and a dopamine D2 receptor antagonist (l-741,626: 0, 0.63, 2.5 µg/side) were infused in the perirhinal cortex (PRh) to block modulation of object recognition memory consolidation induced by 0.4 mg/kg nicotine, 20 mg/kg cocaine, or their CSs. To establish these CSs, male Sprague-Dawley rats were confined for 2 h in a chamber, the CS+, after injections of 0.4 mg/kg nicotine, or 20 mg/kg cocaine, and in another chamber, the CS−, after injections of vehicle. This was repeated over 10 days (5 drug/CS+ and 5 vehicle/CS− pairings in total). It was found that the memory enhancing action of post-sample nicotine was blocked by intra-PRh infusions of both MEC doses, and 30 µg/side MEC also blocked the memory enhancing action of the nicotine CS. Interestingly, intra-PRh MEC did not block the memory enhancing effect of cocaine, nor that of the cocaine CS. In contrast, the memory enhancing action of post-sample cocaine administration was blocked by both l-741,626 doses, and 2.5 µg/side also blocked the effect of the cocaine CS, but not the memory effects of nicotine or of the nicotine CS. This functional double dissociation strongly indicates that drug CSs modulate memory consolidation by activating neural systems that are activated by the drugs themselves.

Transgenerational effects of maternal exposure to nicotine on structures of pituitary-gonadal axis of rats

Smoking can lead to several diseases and cause a reduction in fertility in men and women. Among the various components of cigarettes harmful during pregnancy, nicotine stands out. It can cause a reduction in placental blood flow, compromising the development of the baby with neurological, reproductive and endocrine consequences. Thus, we aimed to evaluate the effects of nicotine on the pituitary-gonadal axis of rats exposed during pregnancy and breastfeeding (1st generation - F1), and whether the possible damage observed would reach the 2nd generation (F2). Pregnant Wistar rats received 2 mg/kg/day of nicotine throughout the entire gestation and lactation. Part of the offspring was evaluated on the first neonatal day (F1) for macroscopic, histopathological and immunohistochemical analyses of brain and gonads. Another part of the offspring was kept until 90 days-old for mating and obtainment of progenies that had the same parameters evaluated at the end of pregnancy (F2). The occurrence of malformations was more frequent and diversified in nicotine-exposed F2. Brain alterations, including reduced size and changes in cell proliferation and death, were seen in both generations of nicotine-exposed rats. Male and female gonads of F1 exposed rats were also affected. The F2 rats showed reduced cellular proliferation and increased cell death on the pituitary and ovaries, besides increased anogenital distance in females. The number of mast cells was not enough altered to indicate an inflammatory process in brain and gonads. We conclude that prenatal exposure to nicotine causes transgenerational alterations in the structures of pituitary-gonadal axis in rats.

Interaction of nicotine and social reward in group-reared male adolescent rats

Adolescents exhibit great sensitivity to nicotine and social interaction; accordingly, when both stimuli are presented together, they interact to enhance the incentive value of the context in which they occur. Noteworthy, most studies assessing the interaction between nicotine and social reward have used isolated-reared rats. Adolescent isolation is an adverse condition that impacts brain development and behavior, so it is not known if the interaction also occurs in rats without social deprivation. The present study used a conditioned place preference model (CPP) to examine the interaction between nicotine and social reward in group-reared male adolescent rats. At weaning, Wistar rats were randomly assigned to four groups: vehicle, vehicle and a social partner, nicotine (0.1 mg/Kg s.c.), and nicotine and a social partner. Conditioning trials occurred on eight consecutive days followed by a test session in which the preference change was assessed. Besides the establishment of CPP, we examined the effects of nicotine on (1) social behaviors during CPP trials and (2) tyrosine hydroxylase (TH) and oxytocin (OT) as markers of changes in the neuronal mechanisms for reward and social affiliation. Similar to previous results, the joint presentation of nicotine and social reward induced CPP, whereas either nicotine or social interaction presented alone did not. This finding coincided with an increase in TH levels observed after nicotine administration only in socially conditioned rats. The interaction between nicotine and social reward is not related to the effects of nicotine on social investigation or social play.

170. Age-Dependent Effects of Tobacco Smoke and Nicotine on Cognition and the Brain: A Systematic Review of the Human and Animal Literature Comparing Adolescents and Adults

170. Age-Dependent Effects of Tobacco Smoke and Nicotine on Cognition and the Brain: A Systematic Review of the Human and Animal Literature Comparing Adolescents and Adults

New insights into how popular electronic cigarette aerosols and aerosol constituents affect SARS-CoV-2 infection of human bronchial epithelial cells

The relationship between the use of tobacco products and SARS-CoV-2 infection is poorly understood and controversial. Few studies have examined the effect of electronic cigarettes (ECs) on SARS-CoV-2 infection. We tested the hypothesis that EC fluids and aerosols with nicotine promote SARS-COV-2 infection by increasing viral entry into human respiratory epithelial cells. Responses of BEAS-2B cells to JUUL aerosols or their individual constituents were compared using three exposure platforms: submerged culture, air–liquid-interface (ALI) exposure in a cloud chamber, and ALI exposure in a Cultex system, which produces authentic heated EC aerosols. In general, nicotine and nicotine + propylene glycol/vegetable glycerin aerosols increased ACE2 (angiotensin converting enzyme 2) levels, the SARS-CoV-2 receptor; and increased the activity of TMPRSS2 (transmembrane serine protease 2), an enzyme essential for viral entry. Lentivirus pseudoparticles with spike protein were used to test viral penetration. Exposure to nicotine, EC fluids, or aerosols altered the infection machinery and increased viral entry into cells. While most data were in good agreement across the three exposure platforms, cells were more responsive to treatments when exposed at the ALI in the Cultex system, even though the exposures were brief and intermittent. While both nicotine and JUUL aerosols increased SARS-CoV-2 infection, JUUL significantly decreased the effect of nicotine alone. These data support the idea that vaping can increase the likelihood of contracting COVID-19 and that e-liquid composition may modulate this effect.

Green Tea Kombucha Increases Leydig Cell Numbers and Testosterone Level in Male Wistar Rats Exposed to Nicotine Electric Cigarette Vapor

Background: Nicotine as a free radical reduces male fertility. Green tea, as an antioxidant, has contributed to protecting testes function; however, green tea kombucha has never been studied for such benefits. This study demonstrated the effect of green tea kombucha in increasing Leydig cells number and testosterone levels in male Wistar rats exposed to nicotine from electric cigarettes. Methods: A post-test-only control group trial was performed on 28 male Wistar rats randomly divided into control, untreated, treatment groups 1 and 2. The control group was exposed to e-cigarette vapor + 1 ml of distilled water. Treatment groups 1 and 2 were exposed to e-cigarette vapor + 0.5 ml/day and 1 ml/day of green tea kombucha, respectively—the e-cigarette vapor exposure occurred daily for 30 minutes. After 28 days, Leydig cell and testosterone levels were measured and compared between groups. Results: The control group's mean value of Leydig cell number is lower than untreated group (p=0.004). Only treatment group 2 had a higher mean of Leydig cell number than control (p<0.001). The control group's mean value for testosterone levels was lower than untreated group (p<0.001). The mean testosterone level in treatment groups 1 and 2 was higher than in untreated and control (p<0.001). In addition, treatment group 2 had higher mean testosterone levels than group 1 (p<0.001). Conclusions: Green tea kombucha has been shown to inhibit the harmful effects of nicotine. These results serve as a basis for the administration of green tea kombucha to prevent free radical-induced testosterone decline. Keywords: Kombucha, Leydig Cells, Testosterone, Nicotine, Antioxidant

Lifetime caffeine and adolescent nicotine exposure in mice: effects on anxiety-like behavior and reward.

Caffeine consumption occurs throughout life, while nicotine use typically begins during adolescence, the period when caffeine-nicotine epidemiological association begins in earnest. Despite that, few studies in animal models parallel the pattern of coexposure that occurs in humans. Therefore, the neurobehavioral consequences of the association between these drugs remain unclear. Here, we exposed Swiss mice to lifetime caffeine. Caffeine solutions of 0.1 g/L (CAF0.1), 0.3 g/L (CAF0.3), or water (CTRL) were used as the sole liquid source, being offered to progenitors until weaning and, after that, directly to the offspring until the last day of adolescent behavioral evaluation. The open field test was used to evaluate acute effects of nicotine, of lifetime caffeine and of their interaction on locomotion and anxiety-like behavior, while the conditioned place preference test was used to assess the impact of caffeine on nicotine (0.5 mg/Kg, i.p.) reward. Frontal cerebral cortex dopamine content, dopamine turnover, and norepinephrine levels, as well as hippocampal serotonin 1A receptor expression were assessed. CAF0.3 mice exhibited an increase in anxiety-like behavior when compared to CAF0.1 and CTRL ones, but nicotine coexposure mitigated the anxiogenic-like caffeine-induced effect. Distinctively, caffeine had no effect on locomotion and failed to interfere with both nicotine-induced hyperactivity and place preference. There were no significant effects on dopaminergic and serotonergic markers. In conclusion, although caffeine did not affect nicotine reward, considering the strong association between anxiety disorders and tobacco consumption, caffeine-induced anxiety-like behavior advises limiting its consumption during development, including adolescence, as caffeine could be a risk factor to nicotine use.

The effect of acute nicotine administration on human delay cued and context fear conditioning.

Nicotine has been shown to facilitate hippocampal-dependent context fear conditioning (FC), but not hippocampal-independent delay cued fear conditioning. Studies examining the effects of nicotine on learned fear have been exclusively limited to nonhumans. The present study aimed to translate nonhuman findings by investigating the effects of nicotine on cued and context fear in humans using a virtual reality (VR) analog of the fear conditioning task. Sixty-seven nicotine-using undergraduates were randomly assigned to receive either a 2 mg nicotine or placebo lozenge prior to conditioning. During conditioning, participants were confined to a virtual room and were conditioned to green floodlight presentations (conditioned stimulus [CS +]) paired with a wrist shock (unconditioned stimulus [US]). A red floodlight served as the CS- during which no shock occurred. Delay cued and context fear testing immediately followed conditioning. Physiological skin conductance responses (SCRs) were recorded continuously throughout all sessions. Nicotine enhanced context fear conditioning such that SCRs to the shock-paired context were significantly greater for the nicotine group than the placebo group. Nicotine did not enhance delay cued fear. Exploratory analyses examining the relationship between fear conditioning and self-reported anxiety revealed that relative to those with lower levels of trait anxiety, nicotine-treated individuals with higher trait anxiety levels were less likely to demonstrate differential conditioning to the shock-paired cue. These findings support abundant nonhuman literature indicating that nicotine facilitates hippocampus-dependent versions of fear conditioning in humans. Results also suggest a role for dysregulated safety learning in pathological anxiety, which may be exacerbated by nicotine use. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Sex Differences in the Impact of Electronic Nicotine Vapor on Corticotropin-Releasing Factor Receptor 1 Neurons in the Mouse Ventral Tegmental Area.

Nicotine engages dopamine neurons in the ventral tegmental area (VTA) to encode reward and drive the development of nicotine addiction, however how nicotine alters a stress associated VTA population remains unclear. Here, we used male and female CRF1-GFP mice and nicotine vapor exposure to examine the effects of nicotine in VTA corticotropin-releasing factor receptor 1 (CRF1) neurons. We use immunohistochemistry and electrophysiology to examine neuronal activity, excitability, and inhibitory signaling. We found that VTA CRF1 neurons are mainly dopaminergic and project to the nucleus accumbens (NAc; VTA-NAcCRF1 neurons). VTA-NAcCRF1 neurons show greater phasic inhibition in naive females and greater focal nicotine-induced increases in firing in naive males. Following acute nicotine vapor exposure, phasic inhibition was not altered, but focal nicotine-induced tonic inhibition was enhanced in females and diminished in males. Acute nicotine vapor exposure did not affect firing in VTA-NAcCRF1 neurons, but females showed lower baseline firing and higher focal nicotine-induced firing. Activity (cFos) was increased in the CRF1 dopaminergic VTA population in both sexes, but with greater increases in females. Following chronic nicotine vapor exposure, both sexes displayed reduced basal phasic inhibition and the sex difference in tonic inhibition following acute vapor exposure was no longer observed. Additionally, activity of the CRF1 dopaminergic VTA population was no longer elevated in either sex. These findings reveal sex-dependent and exposure-dependent changes in mesolimbic VTA-NAc CRF1 neuronal activity, inhibitory signaling, and nicotine sensitivity following nicotine vapor exposure. These changes potentially contribute to nicotine-dependent behaviors and the intersection between stress, anxiety, and addiction.SIGNIFICANCE STATEMENT Nicotine is known to engage reward systems in the brain historically centering the neurotransmitter dopamine however, how nicotine impacts other neurons in the reward pathway is less clear. The current study investigates the impact of acute and chronic electronic nicotine vapor exposure in a genetically-defined cell population containing the stress receptor corticotropin-releasing factor 1 (CRF1) that is located in the reward circuitry. This study employs functional measures of neuronal activity and identifies important sex differences in nicotine's effects across time and exposure.

Nicotine Reduces Reactive Oxygen Species and Enhances Cell Proliferation via the α4 Nicotinic Acetylcholine Receptor Subunit in Human Induced Pluripotent Stem Cells.

The effects of smoking on fetal development and stem cell differentiation are not fully understood. Although nicotinic acetylcholine receptors (nAChRs) are expressed in many organs of the human body, their significance in human induced pluripotent stem cells (hiPSCs) remains unclear. After expression levels of nAChR subunits in hiPSCs were determined, the effects of the nAChR agonist, nicotine, on undifferentiated hiPSCs were evaluated using a Clariom S Array. We also determined the effect of nicotine alone and with a nAChR subunit antagonist on hiPSCs. nAChR α4, α7, and β4 subunits were strongly expressed in hiPSCs. cDNA microarray, gene ontology, and enrichment analyses showed that exposing hiPSCs to nicotine altered expression of genes associated with immune responses, neurological system, carcinogenesis, cell differentiation, and cell proliferation. Particularly affected was metallothionein, which acts to decrease reactive oxygen species (ROS). The nicotine-induced reduction of ROS in hiPSCs was canceled by an α4 subunit or nonselective nAChR antagonist. HiPSC proliferation was increased by nicotine, and this effect, too, was canceled by an α4 antagonist. In conclusion, nicotine reduces ROS and enhances cell proliferation through the α4 nAChR subunit in hiPSCs. These findings provide new insight into the significance of nAChRs on human stem cells and fertilized human ova.

Nicotine- and tar-removed cigarette smoke extract modulates the antigen presentation function of mouse bone marrow-derived dendritic cells.

Dendritic cells (DCs) take up antigens derived from pathogens such as bacteria and viruses, and from tumor cells and induce the activation of antigen-specific T cells through major histocompatibility complex (MHC)-mediated antigen presentation. Mainstream cigarette smoke extract (CSE) has various effects, and the effects of its major components, nicotine and tar, have been extensively analyzed. Recently, the physiological effects of nicotine- and tar-removed CSE (cCSE) have also been reported. However, the effects of cCSE on DC-mediated immune responses remain unknown. In this study, we found that cCSE enhanced lipopolysaccharide (LPS)-stimulated induction of the expression of MHC-I and MHC-II on the cell surface of mouse bone marrow-derived DCs (BMDCs). In contrast, cCSE suppressed the induction of CD86 induced by stimulation with curdlan and interferon-gamma (IFN-γ). In addition, cCSE suppressed the production of IL-12, IL-23, and IL-10 by LPS and curdlan stimulation. In the presence of cCSE, LPS-stimulated BMDCs showed enhanced activation of CD4 and CD8 T cells and increased IL-2 production from T cells by antigen presentation in a mixed-leukocyte reaction assay. In contrast, cCSE did not affect the activation of T cells by curdlan- or IFN-γ-stimulated BMDCs, and curdlan-stimulated BMDCs suppressed IL-17 production from T cells and enhanced IFN-γ production. These results suggest that cCSE has different effects on the activation signals induced by LPS, curdlan, and IFN-γ in BMDCs and modulates the antigen presentation function of BMDCs. This article is protected by copyright. All rights reserved.

Effects of acute and chronic nicotine administration on probability discounting.

Nicotine use is a continuing public health concern. Smokers are more likely to make risky or maladaptive decisions compared to nonsmokers, so the relation between nicotine and risky choice warrants further investigation. Risky choice can be operationally defined as the choice for a larger, uncertain reinforcer over a smaller, certain reinforcer and can be assessed through a probability-discounting procedure. Acute nicotine administration has been shown to alter risky choice, but because the everyday smoker uses nicotine repeatedly, more research on chronic administration is needed and would allow for assessment of tolerance or sensitization of any effects. The present study examined effects of acute and repeated nicotine administration on probability discounting. Sprague-Dawley rats were used as subjects and the probability-discounting task involved discrete-trial choices between a small, certain reinforcer and a larger, uncertain reinforcer. The probability of larger-reinforcer delivery decreased across blocks within each session. Acute nicotine (0.1-1.0 mg/kg) administration dose-dependently increased risky choice, increased lose-stay ratios (a measure of response perseveration), and decreased reinforcement frequency. Tolerance to nicotine's effects on larger-reinforcer choice was observed after repeated 1.0 mg/kg nicotine administration. The results of the present study add to the existing literature that acute nicotine administration increases risky choice and demonstrates that tolerance to this effect develops after chronic exposure to the drug. Possible behavioral mechanisms behind this effect are discussed, as are suggestions for future research on nicotine and risky choice.

Impact of the gut microbiome on nicotine's motivational effects and glial cells in the ventral tegmental area in male mice.

A link between gut dysbiosis and the pathogenesis of brain disorders has been identified. A role for gut bacteria in drug reward and addiction has been suggested but very few studies have investigated their impact on brain and behavioral responses to addictive drugs so far. In particular, their influence on nicotine's addiction-like processes remains unknown. In addition, evidence shows that glial cells shape the neuronal activity of the mesolimbic system but their regulation, within this system, by the gut microbiome is not established. We demonstrate that a lack of gut microbiota in male mice potentiates the nicotine-induced activation of sub-regions of the mesolimbic system. We further show that gut microbiota depletion enhances the response to nicotine of dopaminergic neurons of the posterior ventral tegmental area (pVTA), and alters nicotine's rewarding and aversive effects in an intra-VTA self-administration procedure. These effects were not associated with gross behavioral alterations and the nicotine withdrawal syndrome was not impacted. We further show that depletion of the gut microbiome modulates the glial cells of the mesolimbic system. Notably, it increases the number of astrocytes selectively in the pVTA, and the expression of postsynaptic density protein 95 in both VTA sub-regions, without altering the density of the astrocytic glutamatergic transporter GLT1. Finally, we identify several sub-populations of microglia in the VTA that differ between its anterior and posterior sub-parts, and show that they are re-organized in conditions of gut microbiota depletion. The present study paves the way for refining our understanding of the pathophysiology of nicotine addiction.

Nicotine Exerts a Stronger Immunosuppressive Effect Than Its Structural Analogs and Regulates Experimental Colitis in Rats

Ulcerative colitis (UC) is an intractable disease that causes persistent colonic inflammation. Numerous studies have reported that smoking can afford clinical benefits in UC. This study aimed to elucidate whether nicotine, the main component in cigarettes, can exert pharmacological effects against experimental UC. To achieve this objective, we compared the effects of nicotine with those of structural nicotine analogs in a UC rodent model (Slc: Wistar rats, male, 9-week-old, and 220-250 g/rat). Nicotine, or a respective structural analog (nornicotine, cotinine, anabasine, myosmine, and anatabine), was administered intraperitoneally daily to rats (n = 6/group) exhibiting dextran sulfate sodium-induced experimental colitis. Examining the colon tissues of model rats, we compared disease severity, cytokine secretion, and α7 nicotine acetylcholine receptor (nAChR7) expression. We observed that nicotine administration induced weight loss at 2.35% in 10 days. Notably, the reduction in histological severity (score) of UC was more pronounced in rats treated with nicotine (score = 4.83, p = 0.042) than in untreated rats (score = 8.17). Nicotine administration increased nAChR7 expression 6.88-fold (p = 0.022) in inflammatory sites of the colon, mainly by suppressing the production of interleukin (IL)-1β and IL-6. Moreover, the secretion of these cytokines was suppressed in lipopolysaccharide-stimulated rat macrophages (MΦ) treated with nicotine. In conclusion, nicotine better alleviates experimental UC than the examined structural analogs by activating nAChR7 expression and suppressing proinflammatory cytokines in MΦ.