Prolonged nicotine exposure reduces aversion to the drug in mice by altering nicotinic transmission in the interpeduncular nucleus.

Nicotine intake is likely to result from a balance between the rewarding and aversive properties of the drug, yet the individual differences in neural activity that control aversion to nicotine and their adaptation during the addiction process remain largely unknown. Using a two-bottle choice experiment, we observed a high heterogeneity in nicotine-drinking profiles in isogenic adult male mice, with about half of the mice persisting in consuming nicotine even at high concentrations, whereas the other half durably stopped consumption. We found that nicotine intake was negatively correlated with nicotine-evoked currents in the interpeduncular nucleus (IPN), and that prolonged exposure to nicotine, by weakening this response, decreased aversion to the drug, and hence boosted consumption. Lastly, using knock-out mice and local gene re-expression, we causally identified β4-containing nicotinic acetylcholine receptors of IPN neurons as the molecular and cellular correlates of nicotine aversion. Collectively, our results identify the IPN as a substrate of individual variabilities and adaptations in nicotine consumption.

Genetic Modifiers of Oral Nicotine Consumption in Chrna5 Null Mutant Mice

The gene CHRNA5 is strongly associated with the level of nicotine consumption in humans and manipulation of the expression or function of Chrna5 similarly alters nicotine consumption in rodents. In both humans and rodents, reduced or complete loss of function of Chrna5 leads to increased nicotine consumption. However, the mechanism through which decreased function of Chrna5 increases nicotine intake is not well-understood. Toward a better understanding of how loss of function of Chrna5 increases nicotine consumption, we have initiated efforts to identify genetic modifiers of Chrna5 deletion-dependent oral nicotine consumption in mice. For this, we introgressed the Chrna5 knockout (KO) mutation onto a panel of C57BL/6J-Chr#A/J/NAJ chromosome substitution strains (CSS) and measured oral nicotine consumption in 18 CSS and C57BL/6 (B6) mice homozygous for the Chrna5 KO allele as well as their Chrna5 wild type littermates. As expected, nicotine consumption was significantly increased in Chrna5 KO mice relative to Chrna5 wildtype mice on a B6 background. Among the CSS homozygous for the Chrna5 KO allele, several exhibited altered nicotine consumption relative to B6 Chrna5 KO mice. Sex-independent modifiers were detected in CSS possessing A/J chromosomes 5 and 11 and a male-specific modifier was found on chromosome 15. In all cases nicotine consumption was reduced in the CSS Chrna5 KO mice relative to B6 Chrna5 KO mice and consumption in the CSS KO mice was indistinguishable from their wild type littermates. Nicotine consumption was also reduced in both Chrna5 KO and wildtype CSS mice possessing A/J chromosome 1 and increased in both KO and wild type chromosome 17 CSS relative to KO and wild type B6 mice. These results demonstrate the presence of several genetic modifiers of nicotine consumption in Chrna5 KO mice as well as identify loci that may affect nicotine consumption independent of Chrna5 genotype. Identification of the genes that underlie the altered nicotine consumption may provide novel insight into the mechanism through which Chrna5 deletion increases nicotine consumption and, more generally, a better appreciation of the neurobiology of nicotine intake.

Association of Health Status and Nicotine Consumption with SARS-CoV-2 positivity rates

Background Much of what is known about COVID-19 risk factors comes from patients with serious symptoms who test positive. While risk factors for hospitalization or death include chronic conditions and smoking; less is known about how health status or nicotine consumption is associated with risk of SARS-CoV-2 infection among individuals who do not present clinically. Methods Two community-based population samples (including individuals randomly and nonrandomly selected for statewide testing, n = 8214) underwent SARS-CoV-2 testing in nonclinical settings. Each participant was tested for current (viral PCR) and past (antibody) infection in either April or June of 2020. Before testing, participants provided demographic information and self-reported health status and nicotine and tobacco behaviors (smoking, chewing, vaping/e-cigarettes). Using descriptive statistics and a bivariate logistic regression model, we examined the association between health status and use of tobacco or nicotine with SARS-CoV-2 positivity on either PCR or antibody tests. Results Compared to people with self-identified “excellent” or very good health status, those reporting “good” or “fair” health status had a higher risk of past or current infections. Positive smoking status was inversely associated with SARS-CoV-2 infection. Chewing tobacco was associated with infection and the use of vaping/e-cigarettes was not associated with infection. Conclusions In a statewide, community-based population drawn for SARS-CoV-2 testing, we find that overall health status was associated with infection rates. Unlike in studies of COVID-19 patients, smoking status was inversely associated with SARS-CoV-2 positivity. More research is needed to further understand the nature of this relationship.

Tobacco-related risk behaviors among amateur rugby players, coaches and referees: targets for prevention

Background High prevalence of smoking has been documented in France and new patterns of tobacco and nicotine consumption are emerging, especially in some sports. In amateur rugby population, such attitudes could be harmful, but data are scarce as well as their knowledge of the risk. Purpose We analyzed tobacco consumption in French amateur players, coaches and referees. Methods Each amateur players [>12-y/o], coaches and referees licensed in the French Rugby Federation and participating in the Burgundy amateur championship was invited to answer to an electronic anonymous questionnaire during the 2017–2018 sport season. Results 683 [sex ratio M/F = 0.9] answers were obtained and fit for analysis. Among them, 559 (81.8%) were players, 167 (24,5%) were coaches and 74 (10.8%) were referees. 176 subjects (25.8%) were current smokers, 126 (18.4%) daily smokers, 54 (37% of usual smokers) smoked more than 10 cigarettes a day and 97 (14.2%) were ex-smokers. Moreover, 24 referees (32.4%) and 47 coaches (28.2%) were current smokers. Most smoked 2 hours before or after a rugby session (86.4% of smokers), including coaches (89.4%) and referees (89%). Although 109 smokers (61.9%) considered quitting, only 27 (24.8%) considered vaping to aid them. Only 28 subjects (4.1%) usually vaped, of whom 15 daily (1.9%); 21 of them (75%) vaped in the 2 hours before or after a rugby session. Number of cigarettes in the 19 dual users was not different compared with non-vaping smokers. Among the 28 vapers, motivation to vape included lower risk than smoking (13), consider to quit (12), cheaper than smoking (8), festive and socializing (6), avoid to smoke (3), respect the performance (2). Other tobacco or nicotine products were infrequent: waterpipe (7), dry snuff (1) and none used snus. The knowledge about risk was incomplete: 35 (5.1%) subjects do not know that smoking is dangerous for their health and 12 (1.8%) think it is not. 246 (36%) and 195 (28.6%) do not know if smoking is more dangerous in the 2 hours before or after sport; 45 (6.6%) and 18 (2.6%) think it is not. Moreover, 27.5% of coaches were unaware on the risk of smoking before a sport session and 19.2% on the risk after. 244 subjects (35.7%) do not know if vaping is less dangerous than smoking; 272 (39.8%) are not informed of the potential risk of nicotine when vaping. Conclusion Despite information, prevalence of smoking remains high in the French amateur rugby players, coaches and referees. Smokers usually smoke in the 2 hours before or after the sport session. This is dangerous for them and for their peers. The low knowledge about the CV risk is of great concern, especially when considering the coaches and referees considering both their symbolic position and their educational role. Vaping and other patterns of nicotine exposure are infrequent; none of them use snus. Targeted education programs are urgently needed to reduce acute and chronic risk of tobacco consumption in this population. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): CHU Dijon Bourgogne ARS Bourgogne Franche Comté

Association between cumulative cigarette and Waterpipe smoking and symptoms of dependence in Lebanese adults

Background Waterpipe and cigarette smoking dependence are becoming increasingly prevalent forms of addiction globally. This study examined whether cumulative cigarette smoking and cumulative waterpipe smoking are associated with higher dependence on both cigarettes and waterpipe. Methods This cross-sectional study conducted between February and April 2020, enrolled 363 participants drawn from all Lebanese districts. The mean age was 29.51 years, 64.8% were females, and 124 (34.2%) exclusive cigarette smokers, 189 (52.1%) exclusive waterpipe smokers, and 50 (13.8%) dual smokers (waterpipe and cigarette). We used the Hooked on Nicotine Checklist (HONC) as an indicator of decreased autonomy towards nicotine, in addition to the Lebanon Waterpipe Dependence Scale-11 (LWDS11) and the Lebanese Cigarette Dependence scale (LCD). A stepwise linear regression was performed taking the HONC scores due to cigarette and waterpipe smoking, LCD and LWDS-11 scores as dependent variables. Results The results showed that in the total sample, higher cumulative cigarette smoking (B = 0.005 with a confidence interval of 0.004, 0.006) was significantly associated with higher HONC cigarette scores, whereas higher cumulative waterpipe smoking (B = -0.006 with a confidence interval of − 0.009, − 0.002) was significantly associated with lower HONC cigarette scores. Moreover, higher cumulative waterpipe smoking (B = 0.012 with a confidence interval of 0.009,0.015) was significantly associated with higher HONC waterpipe scores. The results showed that, in both sexes, higher cumulative cigarette smoking was associated with higher HONC cigarette scores and lower HONC waterpipe scores. Furthermore, higher cumulative waterpipe smoking was significantly associated with higher HONC waterpipe scores in both sexes. Conclusion Our study supports the fact that heavy nicotine consumption, related to both the increased frequency and smoking duration, can increase the risk of dependence. It raises the need for strategic plans to minimize and discourage the use of nicotine products in Lebanese community settings.

Heart Rate Variability Changes in Patients With Major Depressive Disorder: Related to Confounding Factors, Not to Symptom Severity?

BackgroundThe aim of this study was to assess the electrophysiological and other influencing factors correlating with symptom severity in patients with major depressive disorder (MDD) under three different conditions: baseline, stress exposure, and relaxation following stress exposure.MethodsSymptom severity was assessed using the Beck Depression Inventory (BDI-II) in 89 inpatients (37 women; mean age 51 years) with MDD. Resting heart rate (RHR), heart rate variability (HRV), respiration rate (RR), skin conductance (SC), and skin temperature (ST) were recorded at baseline for 300 s, under stress exposure for 60 s, and under self-induced relaxation for 300 s. Age, nicotine consumption, body mass index, and blood pressure were evaluated as influencing factors.ResultsThe mean BDI-II mean score was 29.7 points. Disease severity correlated positively with SC elevation under stress exposure and with a lower RR in the relaxed state, but no association was found between HRV and symptom severity. Age and higher blood pressure were both associated with lower HRV and higher RHR.ConclusionThe results indicate that, in patients with MDD, changes in the autonomic nervous system (ANS) are complex; and the assessment of ANS reactivity to stressors is useful. Elevated blood pressure might be underdiagnosed, although it is already relevant in patients with MDD in their early 50s.

Lifestyle modifications after the diagnosis of gynecological cancer

Background The influence of lifestyle factors on the quality of life, incidence and tumor recurrence has been evaluated in several studies and is gaining increasing importance in cancer research. However, the extent of the influence of such lifestyle factors on the quality of life of cancer patients remains largely unclear, as does the number of patients actually pursuing these lifestyle changes. The purpose of this study was to examine the prevalence and predictors of lifestyle changes in patients with gynecological cancer. Methods The survey consisted of a pseudonymous questionnaire that was conducted from January to May 2014 via a telephone interview with 141 patients with a gynaecological malignancy who had undergone surgery at our Department of Gynaecology and Obstetrics. Lifestyle factors (diet, physical activity, stress level, alcohol and nicotine consumption) prior to and after the diagnosis of cancer were evaluated. Results 89% (n = 125) of the patients reported lifestyle changes after being diagnosed with cancer. There was a significant association between the implementation of lifestyle changes and age as well as the use of complementary medicine. Nutrition: 66% of the patients (n = 93) consumed more fruit and vegetables and 65% ate less meat (n = 92). Physical activity: 37% (n = 52) reported no change in their exercise routine, 36% (n = 51) described a decrease, 27% (n = 38) an increase in their physical activity. Subjective feeling of stress: 77% of the patients (n = 108) described a reduction in their perceived level of stress. Nicotine consumption: 63% (n = 12) of the 19 patients who were smokers at the time of the diagnosis quit or reduced smoking thereafter. Alcohol consumption: 47% (n = 61/129) of the patients reduced their alcohol consumption. Conclusions Most of the patients from our study group implemented lifestyle changes after being diagnosed with cancer. Prospective randomized trials are needed in order to determine the benefit of lifestyle changes (physical activity, dietary habits and stress reduction) for cancer survivors. The potential impact of lifestyle on the quality of life and the trajectory of the disease should be discussed with all oncological patients.

The Effects of Environmental Adversities on Human Neocortical Neurogenesis Modeled in Brain Organoids

Over the past decades, a growing body of evidence has demonstrated the impact of prenatal environmental adversity on the development of the human embryonic and fetal brain. Prenatal environmental adversity includes infectious agents, medication, and substances of use as well as inherently maternal factors, such as diabetes and stress. These adversities may cause long-lasting effects if occurring in sensitive time windows and, therefore, have high clinical relevance. However, our knowledge of their influence on specific cellular and molecular processes of in utero brain development remains scarce. This gap of knowledge can be partially explained by the restricted experimental access to the human embryonic and fetal brain and limited recapitulation of human-specific neurodevelopmental events in model organisms. In the past years, novel 3D human stem cell-based in vitro modeling systems, so-called brain organoids, have proven their applicability for modeling early events of human brain development in health and disease. Since their emergence, brain organoids have been successfully employed to study molecular mechanisms of Zika and Herpes simplex virus-associated microcephaly, as well as more subtle events happening upon maternal alcohol and nicotine consumption. These studies converge on pathological mechanisms targeting neural stem cells. In this review, we discuss how brain organoids have recently revealed commonalities and differences in the effects of environmental adversities on human neurogenesis. We highlight both the breakthroughs in understanding the molecular consequences of environmental exposures achieved using organoids as well as the on-going challenges in the field related to variability in protocols and a lack of benchmarking, which make cross-study comparisons difficult.

Advanced maternal age and nicotine consumption during pregnancy

Background Nicotine consumption during pregnancy and advanced maternal age are well known independent risk factors for poor pregnancy outcome and therefore serious public health problems. Objectives Considering the ongoing trend of delaying childbirth in our society, this study investigates potential additive effects of nicotine consumption during pregnancy and advanced maternal age on foetal growth. Sample and Methods In a medical record-based study, we analysed the impact of maternal age and smoking behaviour before and during pregnancy on newborn size among 4142 singleton births that took place in Vienna, Austria between 1990 and 1995. Results Birth weight (H=82.176, p<0.001), birth length (H=91.525, p<0.001) and head circumference (H=42.097, p<0.001) differed significantly according to maternal smoking behaviour. For birth weight, the adjusted mean differences between smokers and non-smokers increased from 101.8g for the < 18-year-old mothers to 254.8g for >35 year olds, with the respective values for birth length being 0.6 cm to 0.7cm, for head circumference from 0.3 cm to 0.6 cm. Conclusion Increasing maternal age amplified the negative effects of smoking during pregnancy on newborn parameters. Our findings identify older smoking mothers as a high-risk group which should be of special interest for public health systems.

Disruption of VGLUT1 in cholinergic medial habenula projections increases nicotine self-administration

Cholinergic projections from the medial habenula (MHb) to the interpeduncular nucleus (IPN) have been studied for their complex contributions to nicotine addiction and have been implicated in nicotine reinforcement, aversion, and withdrawal. While it has been established that MHb cholinergic projections co-release glutamate, no direct evidence has demonstrated a role for this specific glutamate projection in nicotine consumption. In the present study, a novel floxed Slc17a7 (VGLUT1) mouse was generated and used to create conditional knockout (cKO) mice that lack VGLUT1 in MHb cholinergic neurons. Histochemical approaches and optogenetics-assisted electrophysiology were used to validate the disruption of VGLUT1 from cholinergic MHb to IPN projections. The mice displayed no gross phenotypic abnormalities and exhibited normal exploratory and locomotor behavior in the open-field assay. However, the loss of VGLUT1-mediated glutamate co-release led to increased nicotine self-administration. These findings indicate that glutamate co-release from ventral MHb cholinergic neurons opposes nicotine consumption and provide additional support for targeting this synapse to develop potential treatments to nicotine addiction.