scholarly journals Effects of a Peripherally Restricted Hybrid Inhibitor of CB1 Receptors and iNOS on Alcohol Drinking Behavior and Alcohol-Induced Endotoxemia

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 5089
Author(s):  
Luis Santos-Molina ◽  
Alexa Herrerias ◽  
Charles N. Zawatsky ◽  
Ozge Gunduz-Cinar ◽  
Resat Cinar ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Alcohol Intake ◽  
Dominant Role ◽  
Drinking Behavior ◽  
Endocannabinoid System ◽  
Cb1 Receptors ◽  
Relative Role ◽  
Inhibitory Function ◽  
Inos Inhibitor

Alcohol consumption is associated with gut dysbiosis, increased intestinal permeability, endotoxemia, and a cascade that leads to persistent systemic inflammation, alcoholic liver disease, and other ailments. Craving for alcohol and its consequences depends, among other things, on the endocannabinoid system. We have analyzed the relative role of central vs. peripheral cannabinoid CB1 receptors (CB1R) using a “two-bottle” as well as a “drinking in the dark” paradigm in mice. The globally acting CB1R antagonist rimonabant and the non-brain penetrant CB1R antagonist JD5037 inhibited voluntary alcohol intake upon systemic but not upon intracerebroventricular administration in doses that elicited anxiogenic-like behavior and blocked CB1R-induced hypothermia and catalepsy. The peripherally restricted hybrid CB1R antagonist/iNOS inhibitor S-MRI-1867 was also effective in reducing alcohol consumption after oral gavage, while its R enantiomer (CB1R inactive/iNOS inhibitor) was not. The two MRI-1867 enantiomers were equally effective in inhibiting an alcohol-induced increase in portal blood endotoxin concentration that was caused by increased gut permeability. We conclude that (i) activation of peripheral CB1R plays a dominant role in promoting alcohol intake and (ii) the iNOS inhibitory function of MRI-1867 helps in mitigating the alcohol-induced increase in endotoxemia.

Decomposing the time-mean Atlantic Meridional Overturning Circulation and its variability with latitude.

2021 ◽  
Author(s):  
Tomas Jonathan ◽  
Mike Bell ◽  
Helen Johnson ◽  
David Marshall
Keyword(s):  
Global Climate ◽  
Dominant Role ◽  
Meridional Overturning Circulation ◽  
Western Boundary ◽  
Relative Role ◽  
Overturning Circulation ◽  
Near Surface ◽  
Boundary Density ◽  
Meridional Overturning

<p>The Atlantic Meridional Overturning Circulations (AMOC) is crucial to our global climate, transporting heat and nutrients around the globe. Detecting  potential climate change signals first requires a careful characterisation of inherent natural AMOC variability. Using a hierarchy of global coupled model  control runs (HadGEM-GC3.1, HighResMIP) we decompose the overturning circulation as the sum of (near surface) Ekman, (depth-dependent) bottom velocity, eastern and western boundary density components, as a function of latitude. This decomposition proves a useful low-dimensional characterisation of the full 3-D overturning circulation. In particular, the decomposition provides a means to investigate and quantify the constraints which boundary information imposes on the overturning, and the relative role of eastern versus western contributions on different timescales. </p><p>The basin-wide time-mean contribution of each boundary component to the expected streamfunction is investigated as a function of depth, latitude and spatial resolution. Regression modelling supplemented by Correlation Adjusted coRrelation (CAR) score diagnostics provide a natural ranking of the contributions of the various components in explaining the variability of the total streamfunction. Results reveal the dominant role of the bottom component, western boundary and Ekman components at short time-scales, and of boundary density components at decadal and longer timescales.</p>

Peripheral analgesia involves cannabinoid receptors

2018 ◽  
Author(s):  
Julie Desroches
Keyword(s):  
Cannabinoid Receptors ◽  
Receptor Gene ◽  
Endocannabinoid System ◽  
Cb1 Receptor ◽  
Pain Modulation ◽  
Cb1 Receptors ◽  
Gene Encoding ◽  
Cannabinoid Type 1 Receptor ◽  
Peripheral Analgesia

This landmark paper by Agarwal and colleagues was published in 2007, when the exact contribution of the activation of the cannabinoid type 1 receptor (CB1) receptors expressed on the peripheral terminals of nociceptors in pain modulation was still uncertain. At that time, while it was clearly demonstrated that the central nervous system (CNS) was involved in the antinociceptive effects induced by the activation of the CB1 receptor, many strains of mice in which the gene encoding the CB1 receptor was deleted by conditional mutagenesis were used to study the specific role of these receptors in pain. Creating an ingenious model of genetically modified mice with a conditional deletion of the CB1 receptor gene exclusively in the peripheral nociceptors, Agarwal and colleagues were the first to unequivocally demonstrate the major role of this receptor in the control of pain at the peripheral level. In fact, these mutant mice lacking CB1 receptors only in sensory neurons (those expressing the sodium channel Nav1.8) have been designed to highlight that CB1 receptors on nociceptors, and not those within the CNS, constitute an important target for mediating local or systemic (but not intrathecal) cannabinoid analgesia. Overall, they have clarified the anatomical locus of cannabinoid-induced analgesia, highlighted the potential significance of peripheral CB1-mediated cannabinoid analgesia, and revealed important insights into how the peripheral endocannabinoid system works in controlling both inflammatory pain and neuropathic pain.

scholarly journals The Role of Alcohol Consumption in Regulating Circulating Levels of Adiponectin: A Prospective Cohort Study

2015 ◽  
Vol 100 (7) ◽  
pp. 2763-2768 ◽  
Author(s):  
Steven Bell ◽  
Annie Britton
Keyword(s):  
Cohort Study ◽  
Alcohol Consumption ◽  
Prospective Cohort Study ◽  
Prospective Cohort ◽  
Alcohol Intake ◽  
Smoking Status ◽  
Change Score ◽  
Cross Sectional ◽  
Circulating Levels

Context: The role of alcohol intake in influencing longitudinal trajectories of adiponectin is unclear. Objective: The objective of the study was to examine the association between alcohol intake and changes in the circulating levels of adiponectin over repeat measures. Design, Setting, and Participants: A prospective cohort study of 2855 men and women (74% men with a mean age of 50 y at baseline) drawn from the Whitehall II study. Data from study phases 3 (1991–1993), 5 (1997–1999), and 7 (2002–2004) were used. Main Outcome Measure: Adiponectin serum concentrations (nanograms per milliliter) were measured, and alcohol intake was defined in terms of number of UK units (1 U = 8 g ethanol) consumed in the previous 7 days on three occasions. Cross-sectional associations between alcohol and adiponectin levels were calculated using linear regression. A bivariate dual-change score model was used to estimate the effect of alcohol intake on upcoming change in adiponectin. Models were adjusted for age, sex, ethnicity, and smoking status. Results: Alcohol consumption was cross-sectionally associated with (log transformed) adiponectin levels (β ranging from .001 to .004, depending on phase and level of adjustment) but was not associated with changes in adiponectin levels over time [γ = −0.002 (SE 0.002), P = 0.246]. Conclusion: Alcohol intake is not associated with changes in circulating adiponectin levels in this cohort. This finding provides evidence that adiponectin levels are unlikely to mediate the relationship between moderate alcohol consumption and reduced risk of type 2 diabetes. It is important to consider dynamic longitudinal relationships rather than cross-sectional associations.

scholarly journals Protective Behavioral Strategies and Alcohol Consumption: The Moderating Role of Drinking-Group Gender Composition

2019 ◽  
Vol 16 (5) ◽  
pp. 900 ◽  
Author(s):  
Carmen Tabernero ◽  
Tamara Gutiérrez-Domingo ◽  
Bárbara Luque ◽  
Olaya García-Vázquez ◽  
Esther Cuadrado
Keyword(s):  
Alcohol Consumption ◽  
Drinking Behavior ◽  
Gender Composition ◽  
Behavioral Strategies ◽  
Negative Consequences ◽  
Protective Behavioral Strategies ◽  
Protective Strategies ◽  
The Relationship ◽  
Moderating Role

: Background. There is international concern about the negative consequences for health related to young people’s alcohol consumption. Peer relationships can play a positive and protective role to cope with risky behaviors associated with alcohol consumption. Objective. This study investigated the influence of protective behavioral strategies (PBS) on alcohol consumption and the moderating role of drinking-group gender composition and drinking-group size. Methods. The sample comprised 286 youths (mean age = 23.49; SD = 2.78; 67.5% female). Participants reported their protective behavioral strategies, their alcohol consumption and the size (overall mean = 7.44; SD = 3.83) and gender composition (62.58% mixed; 19.93% all-female; 9.8% all-male) of their social drinking groups. The mean sizes of mixed, all-female, and all-male groups were 8.27, 5.34, and 6.2, respectively. Results. Data showed that women consume less alcohol and use more protective strategies than men, particularly those strategies directed at avoiding negative consequences. Furthermore, the number of men in a group influences protective strategies and consumption, therefore drinking-group gender composition moderates the relationship between protective strategies and alcohol consumption. The more protective strategies that young adults use, the lower their alcohol consumption. This relationship is moderated by the size of the group. Conclusion. Strategies to prevent risky drinking behavior should focus on both PBS shared by drinking-group members and the training in individual PBS associated with drinking behavior. Finally, taking into account the relationship between drinking-group gender composition and protective behavioral strategies for alcohol consumption, a positive protector role for individual and group habits in relation to alcohol consumption is discussed.

scholarly journals Changes in Alcohol Consumption Among a Population Who Underwent Medical Checkups During the First Wave of the Coronavirus Disease 2019 Pandemic in Japan: A Single-Center Retrospective Study

2022 ◽  
Vol 22 (3) ◽  
pp. 169-173
Author(s):  
Yusaku Kajihara
Keyword(s):  
Retrospective Study ◽  
Alcohol Consumption ◽  
Alcohol Intake ◽  
Drinking Behavior ◽  
Limited Information ◽  
Excessive Alcohol Consumption ◽  
Excessive Alcohol ◽  
Male Sex ◽  
Lifestyle Related Diseases

Background: Movement restrictions during the coronavirus disease 2019 (COVID-19) pandemic have inflicted stress and affected drinking behavior. However, limited information is available on the changes in alcohol use among the Japanese population.Method: This retrospective study included 371 subjects aged 20–74 years who underwent medical checkups at Fuyoukai Murakami Hospital before (April 1, 2019 to December 31, 2019) and during the COVID-19 pandemic (April 1, 2020 to May 31, 2020). All data were extracted from medical records. Changes in alcohol consumption and severity were also investigated. A logistic regression model was used to identify the risk factors associated with increased drinking, and seven variables were sequentially introduced into the model—age (≤ 49 years), male sex, prior instructions for alcohol restriction, medication for lifestyle-related diseases (e.g., hypertension, dyslipidemia, type 2 diabetes mellitus, and hyperuricemia), depression or insomnia, essential workers, and smoking.Results: The median age was 46 years, and 81.7% subjects were men. In total, 25.1% subjects increased their alcohol intake, and 24.5% subjects reduced their alcohol intake. The rates of excessive alcohol consumption (≥ 60 g ethanol per day) were 15.9% and 16.7% in the pre-COVID-19 period and during the COVID-19 pandemic, respectively. Multivariate analysis identified only age ≤ 49 years as a risk factor for increased drinking (adjusted odds ratio, 2.20; 95% confidence interval, 1.22–3.99; p = 0.009).Conclusion: Approximately one-fourth of the subjects reported increased drinking, although the overall severity remained stable. The importance of alcohol reduction, particularly among young people, should be emphasized.

scholarly journals Finding the Right Balance: A Social Norms Intervention to Reduce Heavy Drinking in University Students

2021 ◽  
Vol 9 ◽  
Author(s):  
Christine Wolter ◽  
Tino Lesener ◽  
Tobias Alexander Thomas ◽  
Alicia-Carolin Hentschel ◽  
Burkhard Gusy
Keyword(s):  
Alcohol Consumption ◽  
University Students ◽  
Social Norms ◽  
Alcohol Intake ◽  
Drinking Behavior ◽  
Intervention Group ◽  
Control Group ◽  
Alcohol Prevention ◽  
Normative Feedback ◽  
The Impact

Introduction: Heavy alcohol consumption constitutes a major health risk among University students. Social relationships with peers strongly affect University students' perception of the drinking behavior of others, which in turn plays a crucial role in determining their own alcohol intake. University students tend to overestimate their peers' alcohol consumption – a belief that is associated with an increase in an individual's own consumption. Therefore, we implemented a social norms intervention with personalized normative feedback at a major University in Germany to reduce and prevent excessive drinking among University students.Methods: Our intervention was part of a regular health monitoring survey. We invited all enrolled University students to take part in this survey on two occasions. A total of 862 University students completed the questionnaire, 563 (65.3%) of which received e-mail-based feedback upon request concerning their peers' and their own alcohol consumption. For the intervention group (n = 190) as well as the control group (no feedback requested; n = 101), we included only University students in the evaluation who overestimated their peers' alcohol use and indicated above average consumption of the peers. We applied analyses of variance to assess intervention effects with regard to the correction of overestimated group norms as well as University students' drinking behavior.Results: Within the intervention group, we observed a significantly larger reduction of the previously overestimated behavioral norms compared to the control group (p < 0.001; ηp2 = 0.06). With regard to behavioral outcomes the intervention group showed a significantly larger reduction in the AUDIT-C score (p = 0.020; ηp2 = 0.03).Discussion: Our study confirms previous research whereupon personalized, gender-specific and selective normative feedback is effective for alcohol prevention among University students. However, University students still overestimated their peers' alcohol intake after the intervention. Furthermore, we did not reach high-risk groups (University students with the highest alcohol intake) since no feedback was requested. Future studies should address factors influencing the impact of the intervention and reachability of selective groups.

scholarly journals A Smartphone App to Assess Alcohol Consumption Behavior: Development, Compliance, and Reactivity (Preprint)

2018 ◽  
Author(s):  
Antoinette Poulton ◽  
Jason Pan ◽  
Loren Richard Bruns Jr ◽  
Richard O Sinnott ◽  
Robert Hester
Keyword(s):  
Alcohol Consumption ◽  
Alcohol Intake ◽  
Drinking Behavior ◽  
Experimental Period ◽  
Smartphone App ◽  
Healthy Population ◽  
Smartphone Apps ◽  
Group Status ◽  
Consumption Behavior ◽  
Study Protocols

BACKGROUND There are disadvantages—largely related to cost, participant burden, and missing data—associated with traditional electronic methods of assessing drinking behavior in real time. This potentially diminishes some of the advantages—namely, enhanced sample size and diversity—typically attributed to these methods. Download of smartphone apps to participants’ own phones might preserve these advantages. However, to date, few researchers have detailed the process involved in developing custom-built apps for use in the experimental arena or explored methodological concerns regarding compliance and reactivity. OBJECTIVE The aim of this study was to describe the process used to guide the development of a custom-built smartphone app designed to capture alcohol intake behavior in the healthy population. Methodological issues related to compliance with and reactivity to app study protocols were examined. Specifically, we sought to investigate whether hazard and nonhazard drinkers would be equally compliant. We also explored whether reactivity in the form of a decrease in drinking or reduced responding (“yes”) to drinking behavior would emerge as a function of hazard or nonhazard group status. METHODS An iterative development process that included elements typical of agile software design guided the creation of the CNLab-A app. Healthy individuals used the app to record alcohol consumption behavior each day for 21 days. Submissions were either event- or notification-contingent. We considered the size and diversity of the sample, and assessed the data for evidence of app protocol compliance and reactivity as a function of hazard and nonhazard drinker status. RESULTS CNLab-A yielded a large and diverse sample (N=671, mean age 23.12). On average, participants submitted data on 20.27 (SD 1.88) out of 21 days (96.5%, 20.27/21). Both hazard and nonhazard drinkers were highly compliant with app protocols. There were no differences between groups in terms of number of days of app use (P=.49) or average number of app responses (P=.54). Linear growth analyses revealed hazardous drinkers decreased their alcohol intake by 0.80 standard drinks over the 21-day experimental period. There was no change to the drinking of nonhazard individuals. Both hazard and nonhazard drinkers showed a slight decrease in responding (“yes”) to drinking behavior over the same period. CONCLUSIONS Smartphone apps participants download to their own phones are effective and methodologically sound means of obtaining alcohol consumption information for research purposes. Although further investigation is required, such apps might, in future, allow for a more thorough examination of the antecedents and consequences of drinking behavior.

Deep brain stimulation of the nucleus accumbens reduces alcohol intake in alcohol-preferring rats

2010 ◽  
Vol 29 (2) ◽  
pp. E12 ◽  
Author(s):  
Michael B. Henderson ◽  
Alan I. Green ◽  
Perry S. Bradford ◽  
David T. Chau ◽  
David W. Roberts ◽  
...  
Keyword(s):  
Deep Brain Stimulation ◽  
Nucleus Accumbens ◽  
Alcohol Consumption ◽  
Brain Stimulation ◽  
Alcohol Intake ◽  
Drugs Of Abuse ◽  
Alcohol Preference ◽  
Stable Pattern ◽  
Deep Brain

Object The authors tested the hypothesis that deep brain stimulation (DBS) in the nucleus accumbens (NAcc) decreases alcohol intake in alcohol-preferring (P) rats after each animal has established a stable, large alcohol intake and after P rats with an established intake have been deprived of alcohol for 4–6 weeks. Methods Bipolar stimulating electrodes were bilaterally placed in the NAcc using stereotactic coordinates. In the first study, P rats (9 animals) were allowed to establish a stable pattern of alcohol intake (about 5–7 g/day) over approximately 2 weeks, and the acute effects of DBS in the NAcc (140–150 Hz, 60-μsec pulse width, and 200-μA current intensity) on alcohol intake and alcohol preference were studied. Each animal acted as its own control and received 1 hour of DBS followed by 1 hour of sham-DBS or vice versa on each of 2 sequential days. The order of testing (sham-DBS vs DBS) was randomized. In the second study, each animal was allowed to establish a stable alcohol intake and then the animal was deprived of alcohol for 4–6 weeks. Animals received DBS (6 rats) or sham-DBS (5 rats) in the NAcc for 24 hours starting when alcohol was reintroduced to each animal. Results Deep brain stimulation in the NAcc, as compared with a period of sham-DBS treatment in the same animals, acutely decreased alcohol preference. Furthermore, alcohol consumption and preference were significantly reduced in the DBS group compared with the sham treatment group during the first 24 hours that alcohol was made available after a period of forced abstinence. Conclusions The NAcc plays a key role in the rewarding and subsequent addictive properties of drugs of abuse in general and of alcohol in particular. Deep brain stimulation in the NAcc reduced alcohol consumption in P rats both acutely and after a period of alcohol deprivation. Therefore, DBS in the NAcc coupled with other neurophysiological measurements may be a useful tool in determining the role of the NAcc in the mesocorticolimbic reward circuit. Deep brain stimulation in the NAcc may also be an effective treatment for reducing alcohol consumption in patients who abuse alcohol and have not responded to other forms of therapy.

scholarly journals Dynamical heating of the X-ray emitting intracluster medium: the roles of merger shocks and turbulence dissipation

2020 ◽  
Vol 495 (1) ◽  
pp. 784-795 ◽  
Author(s):  
Xun Shi ◽  
Daisuke Nagai ◽  
Han Aung ◽  
Andrew Wetzel
Keyword(s):  
Temperature Increase ◽  
Dominant Role ◽  
Tracer Particle ◽  
Dissipative Heating ◽  
Relative Role ◽  
Intracluster Medium ◽  
Time Step ◽  
X Ray ◽  
Accretion Shock

ABSTRACT The diffuse plasma inside clusters of galaxies has X-ray emitting temperatures of a few keV. The physical mechanisms that heat this intracluster medium (ICM) to such temperatures include the accretion shock at the periphery of a galaxy cluster, the shocks driven by merger events, as well as a somewhat overlooked mechanism – the dissipation of intracluster turbulent motions. We study the relative role of these heating mechanisms using galaxy clusters in Lagrangian tracer particle re-simulations of the Omega500 cosmological simulation. We adopt a novel analysis method of decomposing the temperature increase at each time-step into the contribution from dissipative heating and that from adiabatic heating. In the high-resolution spatial–temporal map of these heating rates, merger tracks are clearly visible, demonstrating the dominant role of merger events in heating the ICM. The dissipative heating contributed by each merger event is extended in time and also occurs in the rarefaction regions, suggesting the importance of heating by the dissipation of merger-induced turbulence. Quantitative analysis shows that turbulence heating, rather than direct heating at merger shocks, dominates the temperature increase of the ICM especially at inner radii r < r500c. In addition, we find that many merger shocks can propagate with almost constant velocity to very large radii r ≫ r500c, some even reach and join with the accretion shock and becoming the outer boundary of the ICM. Altogether, these results suggest that the ICM is heated more in an ‘inside–out’ fashion rather than ‘outside–in’ as depicted in the classical smooth accretion picture.

scholarly journals Toll-like receptor 3 activation increases voluntary alcohol intake in C57BL/6J male mice

2018 ◽  
Author(s):  
Anna S. Warden ◽  
Moatasem M. Azzam ◽  
Adriana DaCosta ◽  
Sonia Mason ◽  
Yuri A. Blednov ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Alcohol Drinking ◽  
Alcohol Intake ◽  
Drinking Behavior ◽  
Ethanol Exposure ◽  
Innate Immune ◽  
Poly I:C ◽  
List Type ◽  
Toll Like Receptor ◽  
Excessive Alcohol

AbstractMany genes differentially expressed in brain tissue from human alcoholics and animals that have consumed large amounts of alcohol are components of the innate immune toll-like receptor (TLR) pathway. TLRs initiate inflammatory responses via two branches: (1) MyD88-dependent or (2) TRIF-dependent. All TLRs signal through MyD88 except TLR3. Prior work demonstrated a direct role for MyD88-dependent signaling in regulation of alcohol consumption. However, the role of TLR3 as a potential regulator of excessive alcohol drinking has not previously been investigated. To test the possibility TLR3 activation regulates alcohol consumption, we injected mice with the TLR3 agonist polyinosinic:polycytidylic acid (poly(I:C)) and tested alcohol consumption in an every-other-day two-bottle choice test. Poly(I:C) produced a persistent increase in alcohol intake that developed over several days. Repeated poly(I:C) and ethanol exposure altered innate immune transcript abundance; increased levels of TRIF-dependent pathway components correlated with increased alcohol consumption. Administration of poly(I:C) before exposure to alcohol did not alter alcohol intake, suggesting that poly(I:C) and ethanol must be present together to change drinking behavior. To determine which branch of TLR signaling mediates poly(I:C)-induced changes in drinking behavior, we tested either mice lacking MyD88 or mice administered a TLR3/dsRNA complex inhibitor. MyD88 null mutants showed poly(I:C)-induced increases in alcohol intake. In contrast, mice pretreated with a TLR3/dsRNA complex inhibitor reduced their alcohol intake, suggesting poly(I:C)-induced escalations in alcohol intake function are, at least partially, dependent on TLR3. Together, these results strongly suggest that TLR3-dependent signaling drives excessive alcohol drinking behavior.HighlightsActivation of TLR3 via poly(I:C) increased alcohol intake.Poly(I:C) and ethanol must be present together to change drinking behavior.Increased alcohol intake due to poly(I:C) is independent of MYD88.Increased alcohol intake due to poly(I:C) is dependent on TLR3.

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