Endogenous cholinergic inputs and local circuit mechanisms govern the phasic mesolimbic dopamine response to nicotine

Nicotine exerts its reinforcing action by stimulating nicotinic acetylcholine receptors (nAChRs) and boosting dopamine (DA) output from the ventral tegmental area (VTA). Recent data have led to a debate about the principal pathway of nicotine action: direct stimulation of the DAergic cells through nAChR activation, or disinhibition mediated through desensitization of nAChRs on GABAergic interneurons. We use a computational model of the VTA circuitry and nAChR function to shed light on this issue. Our model illustrates that the α4β2-containing nAChRs either on DA or GABA cells can mediate the acute effects of nicotine. We account for in vitro as well as in vivo data, and predict the conditions necessary for either direct stimulation or disinhibition to be at the origin of DA activity increases. We propose key experiments to disentangle the contribution of both mechanisms. We show that the rate of endogenous acetylcholine input crucially determines the evoked DA response for both mechanisms. Together our results delineate the mechanisms by which the VTA mediates the acute rewarding properties of nicotine and suggest an acetylcholine dependence hypothesis for nicotine reinforcement.Peer reviewe

The Abca7V1613M variant reduces Aβ generation, plaque load, and neuronal damage

BackgroundVariants in ABCA7, a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD).MethodsCRISPR-Cas9 was used to generate an Abca7V1613M variant in mice, modeling the homologous human ABCA7V1599M variant, and extensive characterization was performed.ResultsAbca7V1613M microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity. Homozygous Abca7V1613M mice display elevated circulating cholesterol and altered brain lipid composition. When crossed with 5xFAD mice, homozygous Abca7V1613M mice display fewer Thioflavin S-positive plaques, decreased amyloid beta (Aβ) peptides, and altered amyloid precursor protein processing and trafficking. They also exhibit reduced Aβ-associated inflammation, gliosis, and neuronal damage.DiscussionOverall, homozygosity for the Abca7V1613M variant influences phagocytosis, response to inflammation, lipid metabolism, Aβ pathology, and neuronal damage in mice. This variant may confer a gain of function and offer a protective effect against Alzheimer's disease-related pathology.HighlightsABCA7 recognized as a top 10 risk gene for developing Alzheimer's disease. Loss of function mutations result in increased risk for LOAD. V1613M variant reduces amyloid beta plaque burden in 5xFAD mice. V1613M variant modulates APP processing and trafficking in 5xFAD mice. V1613M variant reduces amyloid beta-associated damage in 5xFAD mice

Review of epidemiologic data on the debate over smokeless tobacco's role in harm reduction

Some tobacco researchers have argued that the European Union should remove its ban on a form of low-nitrosamine smokeless tobacco referred to as Swedish 'snus'. This argument has developed in to an international debate over the use of smokeless tobacco as a measure of harm reduction for smokers. Leading authorities in the USA have firmly stated that there is no safe tobacco - a message which does not allow for any discussion of comparative tobacco risks. This commentary is intended to review the origin of the controversy over Swedish 'snus', to examine briefly the meta-analysis on cancer risks by Peter Lee and Jan Hamling (published in July in BMC Medicine) and to discuss the anticipated direction of the debate on tobacco-harm reduction in the USA. We anticipate that much of the debate will shift from the discussion of epidemiologic data to the discussion of the marketing, health communication and economics of smokeless tobacco. While the Food and Drug Administration's newly approved authority over tobacco will undoubtedly affect the smokeless products, it may not be the sole determinant of harm reduction's fate in the USA

Altering the Motivational Function of Nicotine through Conditioning Processes

The collection of chapters in this 55th Nebraska Symposium on Motivation Volume clearly highlights that effective strategies for reducing compulsive tobacco use will require a multifaceted approach in which genetic, neurobiological, individual, and cultural factors are considered. It is difficult, if not impossible, to predict where the next important breakthrough will come from (Bevins & Bardo, 2004; Dethier, 1966; Laidler, 1998). Accordingly, further research that extends and challenges current theory and practice at each of these levels of analysis is needed. The continuing focus of our research program, and the topic of the present chapter, is on the role of Pavlovian conditioning processes involving nicotine. Theoretical and empirical approaches to nicotine dependence that include Pavlovian conditioning processes have lead to important advances in our understanding and treatment of chronic tobacco use (e.g., see Rose, Chapter 8 and Tiffany, Warthen, & Goedecker, Chapter 10 in current Volume). These approaches conceptualize the drug as an unconditioned stimulus (US) or reinforcer. That is, the pharmacological effects of the drug (e.g., reward, analgesia, psychomotor stimulation) enter into an association with stimuli that reliably co-occur with these effects (e.g., paraphernalia, situational cues). Later exposure to these conditioned stimuli (CSs) can evoke conditioned responses (CRs) that increase the chances an individual will seek drug. More recently, we have suggested that the interoceptive stimulus effects of nicotine might also serve as a CS for other appetitive non-drug outcomes (i.e., USs) and/or a stimulus that occasions whether other CS-US associations will or will not occur (i.e., an occasion setter or facilitator; see Bevins & Palmatier, 2004). We have further suggested that such an associative learning history could impact the tenacity of nicotine addiction—e.g., shorten the time between experimentation and dependence, increase the difficulty of quitting, make sustaining abstinence more difficult, etc. At the current time these suggestions are speculative. With this in mind, the present chapter will review the research in this area, as well as highlight some of its historical precursors and suggest some possible future directions for research. In doing so, hopefully the reader will gain an appreciation for how this approach might lead to further insight into how Pavlovian conditioning processes can alter the motivational function of nicotine in a manner that contributes to chronic tobacco use

Examining the effectiveness of general practitioner and nurse promotion of electronic cigarettes versus standard care for smoking reduction and abstinence in hardcore smokers with smoking-related chronic disease:protocol for a randomised controlled trial

BACKGROUND: Despite the clear harm associated with smoking tobacco, many people with smoking-related chronic diseases or serious mental illnesses (SMI) are unwilling or unable to stop smoking. In many cases, these smokers have tried and exhausted all methods to stop smoking and yet clinicians are repeatedly mandated to offer them during routine consultations. Providing nicotine through electronic cigarettes (e-cigarettes) may reduce the adverse health consequences associated with tobacco smoking, but these are not currently offered. The aim of this study is to examine the feasibility, acceptability and effectiveness of general practitioners (GPs) and nurses delivering a brief advice intervention on e-cigarettes and offering an e-cigarette starter pack and patient support resources compared with standard care in smokers with smoking-related chronic diseases or SMI who are unwilling to stop smoking. METHODS/DESIGN: This is an individually randomised, blinded, two-arm trial. Smokers with a smoking-related chronic condition or SMI with no intention of stopping smoking will be recruited through primary care registers. Eligible participants will be randomised to one of two groups if they decline standard care for stopping smoking: a control group who will receive no additional support beyond standard care; or an intervention group who will receive GP or nurse-led brief advice about e-cigarettes, an e-cigarette starter pack with accompanying practical support booklet, and telephone support from experienced vapers and online video tutorials. The primary outcome measures will be smoking reduction, measured through changes in cigarettes per day and 7-day point-prevalence abstinence at 2 months. Secondary outcomes include smoking reduction, 7-day point-prevalence abstinence and prolonged abstinence at 8 months. Other outcomes include patient recruitment and follow-up, patient uptake and use of e-cigarettes, nicotine intake, contamination of randomisation and practitioner adherence to the delivery of the intervention. Qualitative interviews will be conducted in a subsample of practitioners, patients and the vape team to garner their reactions to the programme. DISCUSSION: This is the first randomised controlled trial to investigate whether e-cigarette provision alongside a brief intervention delivered by practitioners leads to reduced smoking and abstinence among smokers with smoking-related chronic diseases or SMI. TRIAL REGISTRATION: ISRCTN registry, ISRCTN59404712. Registered 28/11/17

Is There Any Association between Use of Smokeless Tobacco Products and Coronary Heart Disease in Bangladesh?

BACKGROUND: Most epidemiological studies exploring the association between smokeless tobacco (SLT) use and coronary heart disease (CHD) have been in Western populations, and have focused on SLT products used in those countries. Few studies come from South Asian countries. Our objective was to determine the association between SLT use and CHD among non-smoking adults in Bangladesh. METHODS: A matched case-control study of non-smoking Bangladeshi adults aged 40–75 years was conducted in 2010. Incident cases of CHD were selected from two cardiac hospitals. Community controls, matched to CHD cases, were selected from neighbourhoods, and hospital controls were selected from outpatient departments of the same hospitals. The Rose Angina Questionnaire (RAQ) was also used to re-classify cases and controls. RESULTS: The study enrolled 302 cases, 1,208 community controls and 302 hospital controls. Current use was higher among community controls (38%) compared to cases (33%) and hospital controls (32%). Current use of SLT was not significantly associated with an increased risk of CHD when community controls were used (adjusted OR 0.87, 95% CI 0.63–1.19), or when hospital controls were used (adjusted OR 1.00, 95% CI 0.63–1.60), or when both control groups were combined (adjusted OR 1.00, 95% CI 0.74–1.34). Risk of CHD did not increase with use of individual types except gul, frequency, duration, past use of SLT products, or using the RAQ to re-classify cases and controls. There was a significant association between gul use and CHD when both controls were combined (adjusted OR 2.93, 95% CI 1.28–6.70). CONCLUSIONS: There was no statistically significant association between SLT use in general and CHD among non-smoking adults in Bangladesh. Further research on the association between gul use and CHD in Bangladesh along with SLT use and CHD in other parts of the subcontinent will guide public health policy and interventions that focus on SLT-related diseases.Muhammad Azia Rahman, Nicola Spurrier, Mohammad Afzal Mahmood, Mahmudur Rahman, Soehl Reza Choudhury and Stephen Leede

Patterns and correlates of tobacco control behavior among american association of pediatric dentistry members: a cross-sectional national study

<p>Abstract</p> <p>Background</p> <p>To determine the tobacco-related knowledge, attitudes, and practice behaviors among US pediatric dentists.</p> <p>Methods</p> <p>A survey was conducted in 1998 among a national, random sample of 1500 American Academy of Pediatric Dentistry members. Chi-square tests and logistic regression with odds ratios (ORs) and 95% confidence intervals assessed factors related to pediatric dentists' tobacco control behaviors.</p> <p>Results</p> <p>Response was 65% for the survey. Only 12% of respondents had prior tobacco prevention/cessation training. Of those untrained, 70% were willing to be trained. Less than two-thirds correctly answered any of four tobacco-related knowledge items. Over one-half agreed pediatric dentists should engage in tobacco control behaviors, but identified patient resistance as a barrier. About 24% of respondents reported always/often asking their adolescent patients about tobacco use; 73% reported always/often advising known tobacco users to quit; and 37% of respondents always/often assisting with stopping tobacco use. Feeling prepared to perform tobacco control behaviors (ORs = 1.9–2.8), a more positive attitude score (4 points) from 11 tobacco-related items (ORs = 1.5–1.8), and a higher statewide tobacco use prevalence significantly predicted performance of tobacco control behaviors.</p> <p>Conclusion</p> <p>Findings suggest thatraining programs on tobacco use and dependence treatment in the pediatric dental setting may be needed to promote tobacco control behaviors for adolescent patients.</p

Salivary cotinine concentrations in daily smokers in Barcelona, Spain: a cross-sectional study

Background: Characterizing and comparing the determinant of cotinine concentrations in different populations should facilitate a better understanding of smoking patterns and addiction. This study describes and characterizes determinants of salivary cotinine concentration in a sample of Spanish adult daily smoker men and women. Methods: A cross-sectional study was carried out between March 2004 and December 2005 in a representative sample of 1245 people from the general population of Barcelona, Spain. A standard questionnaire was used to gather information on active tobacco smoking and passive exposure, and a saliva specimen was obtained to determine salivary cotinine concentration. Two hundred and eleven adult smokers (>16 years old) with complete data were included in the analysis. Determinants of cotinine concentrations were assessed using linear regression models. Results: Salivary cotinine concentration was associated with the reported number of cigarettes smoked in the previous 24 hours (R2 = 0.339; p < 0.05). The inclusion of a quadratic component for number of cigarettes smoked in the regression analyses resulted in an improvement of the fit (R2 = 0.386; p < 0.05). Cotinine concentration differed significantly by sex, with men having higher levels. Conclusion: This study shows that salivary cotinine concentration is significantly associated with the number of cigarettes smoked and sex, but not with other smoking-related variables

Developmental Sex Differences in Nicotinic Currents of Prefrontal Layer VI Neurons in Mice and Rats

There is a large sex difference in the prevalence of attention deficit disorder; yet, relatively little is known about sex differences in the development of prefrontal attention circuitry. In male rats, nicotinic acetylcholine receptors excite corticothalamic neurons in layer VI, which are thought to play an important role in attention by gating the sensitivity of thalamic neurons to incoming stimuli. These nicotinic currents in male rats are significantly larger during the first postnatal month when prefrontal circuitry is maturing. The present study was undertaken to investigate whether there are sex differences in the nicotinic currents in prefrontal layer VI neurons during development.Using whole cell recording in prefrontal brain slice, we examined the inward currents elicited by nicotinic stimulation in male and female rats and two strains of mice. We found a prominent sex difference in the currents during the first postnatal month when males had significantly greater nicotinic currents in layer VI neurons compared to females. These differences were apparent with three agonists: acetylcholine, carbachol, and nicotine. Furthermore, the developmental sex difference in nicotinic currents occurred despite male and female rodents displaying a similar pattern and proportion of layer VI neurons possessing a key nicotinic receptor subunit.This is the first illustration at a cellular level that prefrontal attention circuitry is differently affected by nicotinic receptor stimulation in males and females during development. This transient sex difference may help to define the cellular and circuit mechanisms that underlie vulnerability to attention deficit disorder