Role of sensory stimuli and palatability in oral nicotine consumption in mice

Les produits du tabac sont hautement addictifs et leur abus est un problème majeur de santé publique. Chez les humains, cette addiction met en jeu une expérience consommatoire orale avec des composantes sensorielles gustatives et olfactives. De nos jours, le rôle de ces composantes est amplifié avec l’utilisation accrue des produits du tabac non-brûlé, mais aussi les cigarettes électroniques, où la nicotine est associée à des additifs incluant flaveurs et sucres. L’impact des additifs sur le comportement de consommation du tabac doit donc être évalué. Dans ce travail de recherche, notre intérêt se porte sur la nicotine orale et l’interaction bidirectionnelle avec les flaveurs associées. Nous questionnons notamment les propriétés de renforcement secondaire, les effets des arômes sur la palatabilité de la nicotine et son encodage affectif. Dans un premier chapitre, nous avons investigué les propriétés irritantes de la nicotine dans un modèle d’auto-administration orale de nicotine diluée dans de la saccharine chez des souris génétiquement modifiées (knockout) pour le thermorécepteur TRPV1 (Transient receptor potential vanilloid 1), impliqué dans l’échauffement lié au tabagisme et qui a la particularité d’être sensibilisé par la nicotine. Nous mettons en évidence que l’absence de ce récepteur promeut la consommation de nicotine par diminution de son aversion orale. Il n’a cependant pas un rôle spécifique dans les mécanismes de motivation et de rechute. Il a été montré que les stimuli sensoriels non-pharmacologiques deviennent plus salients quand ils sont associés à la nicotine. Ainsi, nous étudions dans un deuxième chapitre, le renforcement secondaire putatif des stimuli oraux par la nicotine. Nous mettons en évidence la nécessité d’association orale de la nicotine à des additifs masquant son goût amer, afin de permettre sa consommation volontaire et la modélisation des différents stades du processus addictif. Ce processus se montre sensible aux stimuli dans la consommation et la rechute, mais insensible aux challenges pharmacologiques malgré l’absorption de nicotine mesurée par la présence de cotinine plasmatique. Les solutions de nicotine à fortes concentrations révèlent des propriétés aversives et réduisent la consommation volontaire. Bien que nous ne montrions pas le renforcement des propriétés incitatives de la vanille par la nicotine, de façon surprenante nous montrons que l’arôme seul peut renforcer le comportement d’auto-administration. Enfin, du fait de l’importance des effets sensoriels oraux dans la consommation de nicotine, nous avons étudié ses propriétés de palatabilité. Les tests de réactivité gustative montrent bien l’aversion gustative pour la nicotine seule et l’amélioration de la palatabilité par l’ajout d’additif aromatique. Ce changement de la palatabilité ne s’est néanmoins pas traduit par des changements du codage neuronal mesuré par le marquage de la protéine c-Fos dans les structures contribuant à l’expression de la valence positive ou négative, notamment le noyau accumbens, le cortex insulaire gustatif, le noyau basolatéral de l’amygdale, l’habenula et la noyau paraventriculaire du thalamus. En revanche, la nicotine, aromatisée ou non, a augmenté l’activation neuronale dans toutes ces structures. L’ensemble de ces résultats met en lumière cette problématique d’association de la nicotine aux additifs pouvant moduler sa perception sensorielle et promouvoir par la suite sa consommation. L’attractivité des nouveaux produits du tabac et leur potentiel d’abus est une question authentique et un problème de santé publique dont l’étude et la régulation sont urgentes.Tobacco products are highly addictive and their abuse is a major public health problem. In humans, this addiction constitutes an oral consummatory experience involving sensory gustatory and olfactory components. Nowadays, the role of these components is further amplified with the increasing use of new “heat not burn” tobacco products, electronic nicotine delivery device (e-cigarettes especially), where nicotine is associated with additives including flavours and sugars. Thus, the impact of additives on the behaviour of nicotine consumption must be assessed. In this research work, we are interested in oral nicotine and the bidirectional interaction with the associated flavours. In particular, we question the secondary reinforcing properties, the effects of aromas on the palatability of nicotine and its affective coding. In a first chapter, we investigated the irritating properties of nicotine in a model of oral self-administration in mice genetically modified (knockout) for the thermoreceptor TRPV1 (Transient receptor potential vanilloid 1) because it is involved in harshness and it is sensitized by nicotine. We highlight that the absence of this receptor promotes nicotine consumption by reducing its oral aversion. It does not, however, have a specific role in motivation and relapse mechanisms. It has been shown that non-pharmacological sensory stimuli become more salient when associated with nicotine. Here, we study the putative secondary reinforcement of oral stimuli by nicotine. We highlight the need for oral nicotine to be combined with additives that mask its bitter taste, to allow its volitional consumption and to be able to model the different stages of the addictive process. This process is sensitive to stimuli for consumption and reinstatement, but is unaffected by pharmacological challenges despite nicotine absorption measured by the dosage of plasma cotinine. High concentrations of nicotine solutions reveal its aversive properties and reduce oral self-administration in mice. Although we do not show the reinforcement of the incentive properties of vanilla by nicotine, we surprisingly show that the aroma itself can reinforce self-administration behaviour. Finally, because of the importance of the oral sensory effects in nicotine consummatory behavior, we studied its palatability properties. Taste reactivity tests show the aversive taste of nicotine alone and the enhancement of its palatability by the addition of aromatic additive. However this change in palatability did not result in changes in the neuronal coding, measured by the labelling of c-Fos protein in brain structures contributing to the expression of the positive and negative valence, notably the nucleus accumbens, the gustatory insular cortex, the basolateral amygdala, the habenula and the paraventricular nucleus of the thalamus. On the other hand, nicotine, flavoured or not, increased neuronal activity in all these structures. Altogether, these results highlight the importance of nicotine association with flavour additives that can modulate its sensory perception and subsequently promote its consumption. The attractiveness of new tobacco products and their abuse potential is a public health problem that needs urgent study and regulation

Rôle des stimuli sensoriels et de la palatabilité dans la prise orale de nicotine chez la souris

Tobacco products are highly addictive and their abuse is a major public health problem. In humans, this addiction constitutes an oral consummatory experience involving sensory gustatory and olfactory components. Nowadays, the role of these components is further amplified with the increasing use of new “heat not burn” tobacco products, electronic nicotine delivery device (e-cigarettes especially), where nicotine is associated with additives including flavours and sugars. Thus, the impact of additives on the behaviour of nicotine consumption must be assessed. In this research work, we are interested in oral nicotine and the bidirectional interaction with the associated flavours. In particular, we question the secondary reinforcing properties, the effects of aromas on the palatability of nicotine and its affective coding. In a first chapter, we investigated the irritating properties of nicotine in a model of oral self-administration in mice genetically modified (knockout) for the thermoreceptor TRPV1 (Transient receptor potential vanilloid 1) because it is involved in harshness and it is sensitized by nicotine. We highlight that the absence of this receptor promotes nicotine consumption by reducing its oral aversion. It does not, however, have a specific role in motivation and relapse mechanisms. It has been shown that non-pharmacological sensory stimuli become more salient when associated with nicotine. Here, we study the putative secondary reinforcement of oral stimuli by nicotine. We highlight the need for oral nicotine to be combined with additives that mask its bitter taste, to allow its volitional consumption and to be able to model the different stages of the addictive process. This process is sensitive to stimuli for consumption and reinstatement, but is unaffected by pharmacological challenges despite nicotine absorption measured by the dosage of plasma cotinine. High concentrations of nicotine solutions reveal its aversive properties and reduce oral self-administration in mice. Although we do not show the reinforcement of the incentive properties of vanilla by nicotine, we surprisingly show that the aroma itself can reinforce self-administration behaviour. Finally, because of the importance of the oral sensory effects in nicotine consummatory behavior, we studied its palatability properties. Taste reactivity tests show the aversive taste of nicotine alone and the enhancement of its palatability by the addition of aromatic additive. However this change in palatability did not result in changes in the neuronal coding, measured by the labelling of c-Fos protein in brain structures contributing to the expression of the positive and negative valence, notably the nucleus accumbens, the gustatory insular cortex, the basolateral amygdala, the habenula and the paraventricular nucleus of the thalamus. On the other hand, nicotine, flavoured or not, increased neuronal activity in all these structures. Altogether, these results highlight the importance of nicotine association with flavour additives that can modulate its sensory perception and subsequently promote its consumption. The attractiveness of new tobacco products and their abuse potential is a public health problem that needs urgent study and regulation.Les produits du tabac sont hautement addictifs et leur abus est un problème majeur de santé publique. Chez les humains, cette addiction met en jeu une expérience consommatoire orale avec des composantes sensorielles gustatives et olfactives. De nos jours, le rôle de ces composantes est amplifié avec l’utilisation accrue des produits du tabac non-brûlé, mais aussi les cigarettes électroniques, où la nicotine est associée à des additifs incluant flaveurs et sucres. L’impact des additifs sur le comportement de consommation du tabac doit donc être évalué. Dans ce travail de recherche, notre intérêt se porte sur la nicotine orale et l’interaction bidirectionnelle avec les flaveurs associées. Nous questionnons notamment les propriétés de renforcement secondaire, les effets des arômes sur la palatabilité de la nicotine et son encodage affectif. Dans un premier chapitre, nous avons investigué les propriétés irritantes de la nicotine dans un modèle d’auto-administration orale de nicotine diluée dans de la saccharine chez des souris génétiquement modifiées (knockout) pour le thermorécepteur TRPV1 (Transient receptor potential vanilloid 1), impliqué dans l’échauffement lié au tabagisme et qui a la particularité d’être sensibilisé par la nicotine. Nous mettons en évidence que l’absence de ce récepteur promeut la consommation de nicotine par diminution de son aversion orale. Il n’a cependant pas un rôle spécifique dans les mécanismes de motivation et de rechute. Il a été montré que les stimuli sensoriels non-pharmacologiques deviennent plus salients quand ils sont associés à la nicotine. Ainsi, nous étudions dans un deuxième chapitre, le renforcement secondaire putatif des stimuli oraux par la nicotine. Nous mettons en évidence la nécessité d’association orale de la nicotine à des additifs masquant son goût amer, afin de permettre sa consommation volontaire et la modélisation des différents stades du processus addictif. Ce processus se montre sensible aux stimuli dans la consommation et la rechute, mais insensible aux challenges pharmacologiques malgré l’absorption de nicotine mesurée par la présence de cotinine plasmatique. Les solutions de nicotine à fortes concentrations révèlent des propriétés aversives et réduisent la consommation volontaire. Bien que nous ne montrions pas le renforcement des propriétés incitatives de la vanille par la nicotine, de façon surprenante nous montrons que l’arôme seul peut renforcer le comportement d’auto-administration. Enfin, du fait de l’importance des effets sensoriels oraux dans la consommation de nicotine, nous avons étudié ses propriétés de palatabilité. Les tests de réactivité gustative montrent bien l’aversion gustative pour la nicotine seule et l’amélioration de la palatabilité par l’ajout d’additif aromatique. Ce changement de la palatabilité ne s’est néanmoins pas traduit par des changements du codage neuronal mesuré par le marquage de la protéine c-Fos dans les structures contribuant à l’expression de la valence positive ou négative, notamment le noyau accumbens, le cortex insulaire gustatif, le noyau basolatéral de l’amygdale, l’habenula et la noyau paraventriculaire du thalamus. En revanche, la nicotine, aromatisée ou non, a augmenté l’activation neuronale dans toutes ces structures. L’ensemble de ces résultats met en lumière cette problématique d’association de la nicotine aux additifs pouvant moduler sa perception sensorielle et promouvoir par la suite sa consommation. L’attractivité des nouveaux produits du tabac et leur potentiel d’abus est une question authentique et un problème de santé publique dont l’étude et la régulation sont urgentes

Role of sensory stimuli and palatability in oral nicotine consumption in mice

Les produits du tabac sont hautement addictifs et leur abus est un problème majeur de santé publique. Chez les humains, cette addiction met en jeu une expérience consommatoire orale avec des composantes sensorielles gustatives et olfactives. De nos jours, le rôle de ces composantes est amplifié avec l’utilisation accrue des produits du tabac non-brûlé, mais aussi les cigarettes électroniques, où la nicotine est associée à des additifs incluant flaveurs et sucres. L’impact des additifs sur le comportement de consommation du tabac doit donc être évalué. Dans ce travail de recherche, notre intérêt se porte sur la nicotine orale et l’interaction bidirectionnelle avec les flaveurs associées. Nous questionnons notamment les propriétés de renforcement secondaire, les effets des arômes sur la palatabilité de la nicotine et son encodage affectif. Dans un premier chapitre, nous avons investigué les propriétés irritantes de la nicotine dans un modèle d’auto-administration orale de nicotine diluée dans de la saccharine chez des souris génétiquement modifiées (knockout) pour le thermorécepteur TRPV1 (Transient receptor potential vanilloid 1), impliqué dans l’échauffement lié au tabagisme et qui a la particularité d’être sensibilisé par la nicotine. Nous mettons en évidence que l’absence de ce récepteur promeut la consommation de nicotine par diminution de son aversion orale. Il n’a cependant pas un rôle spécifique dans les mécanismes de motivation et de rechute. Il a été montré que les stimuli sensoriels non-pharmacologiques deviennent plus salients quand ils sont associés à la nicotine. Ainsi, nous étudions dans un deuxième chapitre, le renforcement secondaire putatif des stimuli oraux par la nicotine. Nous mettons en évidence la nécessité d’association orale de la nicotine à des additifs masquant son goût amer, afin de permettre sa consommation volontaire et la modélisation des différents stades du processus addictif. Ce processus se montre sensible aux stimuli dans la consommation et la rechute, mais insensible aux challenges pharmacologiques malgré l’absorption de nicotine mesurée par la présence de cotinine plasmatique. Les solutions de nicotine à fortes concentrations révèlent des propriétés aversives et réduisent la consommation volontaire. Bien que nous ne montrions pas le renforcement des propriétés incitatives de la vanille par la nicotine, de façon surprenante nous montrons que l’arôme seul peut renforcer le comportement d’auto-administration. Enfin, du fait de l’importance des effets sensoriels oraux dans la consommation de nicotine, nous avons étudié ses propriétés de palatabilité. Les tests de réactivité gustative montrent bien l’aversion gustative pour la nicotine seule et l’amélioration de la palatabilité par l’ajout d’additif aromatique. Ce changement de la palatabilité ne s’est néanmoins pas traduit par des changements du codage neuronal mesuré par le marquage de la protéine c-Fos dans les structures contribuant à l’expression de la valence positive ou négative, notamment le noyau accumbens, le cortex insulaire gustatif, le noyau basolatéral de l’amygdale, l’habenula et la noyau paraventriculaire du thalamus. En revanche, la nicotine, aromatisée ou non, a augmenté l’activation neuronale dans toutes ces structures. L’ensemble de ces résultats met en lumière cette problématique d’association de la nicotine aux additifs pouvant moduler sa perception sensorielle et promouvoir par la suite sa consommation. L’attractivité des nouveaux produits du tabac et leur potentiel d’abus est une question authentique et un problème de santé publique dont l’étude et la régulation sont urgentes.Tobacco products are highly addictive and their abuse is a major public health problem. In humans, this addiction constitutes an oral consummatory experience involving sensory gustatory and olfactory components. Nowadays, the role of these components is further amplified with the increasing use of new “heat not burn” tobacco products, electronic nicotine delivery device (e-cigarettes especially), where nicotine is associated with additives including flavours and sugars. Thus, the impact of additives on the behaviour of nicotine consumption must be assessed. In this research work, we are interested in oral nicotine and the bidirectional interaction with the associated flavours. In particular, we question the secondary reinforcing properties, the effects of aromas on the palatability of nicotine and its affective coding. In a first chapter, we investigated the irritating properties of nicotine in a model of oral self-administration in mice genetically modified (knockout) for the thermoreceptor TRPV1 (Transient receptor potential vanilloid 1) because it is involved in harshness and it is sensitized by nicotine. We highlight that the absence of this receptor promotes nicotine consumption by reducing its oral aversion. It does not, however, have a specific role in motivation and relapse mechanisms. It has been shown that non-pharmacological sensory stimuli become more salient when associated with nicotine. Here, we study the putative secondary reinforcement of oral stimuli by nicotine. We highlight the need for oral nicotine to be combined with additives that mask its bitter taste, to allow its volitional consumption and to be able to model the different stages of the addictive process. This process is sensitive to stimuli for consumption and reinstatement, but is unaffected by pharmacological challenges despite nicotine absorption measured by the dosage of plasma cotinine. High concentrations of nicotine solutions reveal its aversive properties and reduce oral self-administration in mice. Although we do not show the reinforcement of the incentive properties of vanilla by nicotine, we surprisingly show that the aroma itself can reinforce self-administration behaviour. Finally, because of the importance of the oral sensory effects in nicotine consummatory behavior, we studied its palatability properties. Taste reactivity tests show the aversive taste of nicotine alone and the enhancement of its palatability by the addition of aromatic additive. However this change in palatability did not result in changes in the neuronal coding, measured by the labelling of c-Fos protein in brain structures contributing to the expression of the positive and negative valence, notably the nucleus accumbens, the gustatory insular cortex, the basolateral amygdala, the habenula and the paraventricular nucleus of the thalamus. On the other hand, nicotine, flavoured or not, increased neuronal activity in all these structures. Altogether, these results highlight the importance of nicotine association with flavour additives that can modulate its sensory perception and subsequently promote its consumption. The attractiveness of new tobacco products and their abuse potential is a public health problem that needs urgent study and regulation

Baclofen-Induced Neuro-Respiratory Toxicity in the Rat: Contribution of Tolerance and Characterization of Withdrawal Syndrome

International audienc

The Evolution of Effort-Reward Imbalance in Workers during the COVID-19 Pandemic in France - An Observational Study in More than 8000 Workers

International audience(1) Background: The effects of lockdown repetition on work-related stress, expressed through Effort-Reward Imbalance (ERI), during the COVID-19 pandemic are poorly documented. We investigated the effect of repetitive lockdowns on the ERI in French workers, its difference across occupations, and the change in its influencing factors across time. (2) Methods: Participants were included in a prospective cross-sectional observational study from 30 March 2020 to 28 May 2021. The primary outcome was the ERI score (visual analog scale). The ERI score of the population was examined via Generalized Estimating Equations. For each period, the factors influencing ERI were studied by multivariate linear regression. (3) Results: In 8121 participants, the ERI score decreased in the first 2 lockdowns (53.2 ± 0.3, p < 0.001; 50.5 ± 0.7, p < 0.001) and after lockdown 2 (54.8 ± 0.8, p = 0.004) compared with the pre-pandemic period (59 ± 0.4). ERI was higher in medical than in paramedical professionals in the pre-pandemic and the first 2 lockdowns. Higher workloads were associated with better ERI scores. (4) Conclusions: In a large French sample, Effort-Reward Imbalance worsened during the COVID-19 pandemic until the end of the 2nd lockdown. Paramedical professionals experienced a higher burden of stress compared with medical professionals

Phase 2 trial of the DPP-1 inhibitor brensocatib in bronchiectasis

Background: Patients with bronchiectasis have frequent exacerbations that are thought to be related to neutrophilic inflammation. The activity and quantity of neutrophil serine proteases, including neutrophil elastase, are increased in the sputum of patients with bronchiectasis at baseline and increase further during exacerbations. Brensocatib (INS1007) is an oral reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), an enzyme responsible for the activation of neutrophil serine proteases. Methods: In a phase 2, randomized, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1:1 ratio, patients with bronchiectasis who had had at least two exacerbations in the previous year to receive placebo, 10 mg of brensocatib, or 25 mg of brensocatib once daily for 24 weeks. The time to the first exacerbation (primary end point), the rate of exacerbations (secondary end point), sputum neutrophil elastase activity, and safety were assessed. Results: Of 256 patients, 87 were assigned to receive placebo, 82 to receive 10 mg of brensocatib, and 87 to receive 25 mg of brensocatib. The 25th percentile of the time to the first exacerbation was 67 days in the placebo group, 134 days in the 10-mg brensocatib group, and 96 days in the 25-mg brensocatib group. Brensocatib treatment prolonged the time to the first exacerbation as compared with placebo (P = 0.03 for 10-mg brensocatib vs. placebo; P = 0.04 for 25-mg brensocatib vs. placebo). The adjusted hazard ratio for exacerbation in the comparison of brensocatib with placebo was 0.58 (95% confidence interval [CI], 0.35 to 0.95) in the 10-mg group (P = 0.03) and 0.62 (95% CI, 0.38 to 0.99) in the 25-mg group (P = 0.046). The incidence-rate ratio was 0.64 (95% CI, 0.42 to 0.98) in the 10-mg group, as compared with placebo (P = 0.04), and 0.75 (95% CI, 0.50 to 1.13) in the 25-mg group, as compared with placebo (P = 0.17). With both brensocatib doses, sputum neutrophil elastase activity was reduced from baseline over the 24-week treatment period. The incidence of dental and skin adverse events of special interest was higher with the 10-mg and 25-mg brensocatib doses, respectively, than with placebo. Conclusions: In this 24-week trial, reduction of neutrophil serine protease activity with brensocatib in patients with bronchiectasis was associated with improvements in bronchiectasis clinical outcomes

Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies

Background: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. Methods: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Findings: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42·4% vs 44·2%; absolute difference -1·69 [-9·58 to 6·11] p=0·67; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5-8] vs 6 [5-8] cm H2O; p=0·0011). ICU mortality was higher in MICs than in HICs (30·5% vs 19·9%; p=0·0004; adjusted effect 16·41% [95% CI 9·52-23·52]; p&lt;0·0001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0·80 [95% CI 0·75-0·86]; p&lt;0·0001). Interpretation: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status