The effects of moxidectin nicotine-conditioned cue on nicotine-seeking behavior in mice

Current pharmacotherapies for nicotine abuse are few and relatively inefficient demonstrating the need for the development of new, effective remedies. Moxidectin is used as an anti-parasitic agent in both animals and humans, it also activates GABA receptors. The objective of the present investigation was to study the effect of moxidectin on nicotine-induced conditioned place preference (CPP) in male Swiss mice. Intraperitoneal (i.p.) route was used for nicotine (0.5mg/kg) administration for a 3-day conditioning program. The influences of moxidectin on the reinforcing characteristics of nicotine were tested in mice given i.p. treatment of moxidectin (5 and 10mg/kg) 30 minutes prior to per nicotine administration. CPP was extinguished by repeated testing, through which conditioned mice were daily given two doses of moxidectin (5 and 10mg/kg, i.p.). Subsequently, the potency of moxidectin in blocking the reinstatement of CPP provoked by priming given low-dose nicotine (0.1mg/kg, i.p.) was also evaluated. Moxidectin treatment illustrated a reserve of acquisition of nicotine-induced CPP. It was reduced priming nicotine-induced reinstatement and accelerated the extinction of CPP. Relatively nicotine enhanced the locomotor, motor activity but was not statistically significant. In conclusion, the outcomes demonstrate the potential for the development of moxidectin as a new pharmacotherapy for the treatment of nicotine addiction.

The Effect of Cardiovascular Comorbidities on Women Compared to Men: Longitudinal Retrospective Analysis

Background Although men are more prone to developing cardiovascular disease (CVD) than women, risk factors for CVD, such as nicotine abuse and diabetes mellitus, have been shown to be more detrimental in women than in men. Objective We developed a method to systematically investigate population-wide electronic health records for all possible associations between risk factors for CVD and other diagnoses. The developed structured approach allows an exploratory and comprehensive screening of all possible comorbidities of CVD, which are more connected to CVD in either men or women. Methods Based on a population-wide medical claims dataset comprising 44 million records of inpatient stays in Austria from 2003 to 2014, we determined comorbidities of acute myocardial infarction (AMI; International Classification of Diseases, Tenth Revision [ICD-10] code I21) and chronic ischemic heart disease (CHD; ICD-10 code I25) with a significantly different prevalence in men and women. We introduced a measure of sex difference as a measure of differences in logarithmic odds ratios (ORs) between male and female patients in units of pooled standard errors. Results Except for lipid metabolism disorders (OR for females [ORf]=6.68, 95% confidence interval [CI]=6.57-6.79, OR for males [ORm]=8.31, 95% CI=8.21-8.41), all identified comorbidities were more likely to be associated with AMI and CHD in females than in males: nicotine dependence (ORf=6.16, 95% CI=5.96-6.36, ORm=4.43, 95% CI=4.35-4.5), diabetes mellitus (ORf=3.52, 95% CI=3.45-3.59, ORm=3.13, 95% CI=3.07-3.19), obesity (ORf=3.64, 95% CI=3.56-3.72, ORm=3.33, 95% CI=3.27-3.39), renal disorders (ORf=4.27, 95% CI=4.11-4.44, ORm=3.74, 95% CI=3.67-3.81), asthma (ORf=2.09, 95% CI=1.96-2.23, ORm=1.59, 95% CI=1.5-1.68), and COPD (ORf=2.09, 95% CI 1.96-2.23, ORm=1.59, 95% CI 1.5-1.68). Similar results could be observed for AMI. Conclusions Although AMI and CHD are more prevalent in men, women appear to be more affected by certain comorbidities of AMI and CHD in their risk for developing CVD.

LSD-stimulated behaviors in mice require β-arrestin 2 but not β-arrestin 1

Recent evidence suggests that psychedelic drugs can exert beneficial effects on anxiety, depression, and ethanol and nicotine abuse in humans. However, their hallucinogenic side-effects often preclude their clinical use. Lysergic acid diethylamide (LSD) is a prototypical hallucinogen and its psychedelic actions are exerted through the 5-HT2A serotonin receptor (5-HT2AR). 5-HT2AR activation stimulates Gq- and β-arrestin- (βArr) mediated signaling. To separate these signaling modalities, we have used βArr1 and βArr2 mice. We find that LSD stimulates motor activities to similar extents in WT and βArr1-KO mice, without effects in βArr2-KOs. LSD robustly stimulates many surrogates of psychedelic drug actions including head twitches, grooming, retrograde walking, and nose-poking in WT and βArr1-KO animals. By contrast, in βArr2-KO mice head twitch responses are low with LSD and this psychedelic is without effects on other surrogates. The 5-HT2AR antagonist MDL100907 (MDL) blocks the LSD effects. LSD also disrupts prepulse inhibition (PPI) in WT and βArr1-KOs, but not in βArr2-KOs. MDL restores LSD-mediated disruption of PPI in WT mice; haloperidol is required for normalization of PPI in βArr1-KOs. Collectively, these results reveal that LSD’s psychedelic drug-like actions appear to require βArr2.

Lower body lift and abdominal surgery after massive weight loss

Following the establishment of modern body lift procedures by Ted Lockwood, who sadly passed away in 2005, other innovative approaches are also now available. The main idea behind these operations, similar to modern face-lifting procedures, is to reconstruct the superficial and deep tissue layers (comparable to the superficial musculoaponeurotic system of the face) and the overlying skin. Large areas of tissue undermining and separation are, however, necessary to allow sufficient mobilization and tightening to achieve improvement in function and form. At the same time, it should not be forgotten that patients who have undergone major weight loss often have intrinsic medical problems such as diabetes mellitus, high blood pressure, nicotine abuse, and hormonal changes. These factors must be considered when planning the reconstruction. The problems and solutions derive from the authors’ experience over the last 15 years at the Department of Plastic Surgery at the Dreifaltigkeits-Hospital in Wesseling, Germany. These surgical procedures create great wound cavities but have associated risks that are manageable when planning and surgery are carried out meticulously.

Multifactorial Etiology of Adolescent Nicotine Addiction: A Review of the Neurobiology of Nicotine Addiction and Its Implications for Smoking Cessation Pharmacotherapy

Nicotine is the primary pharmacologic component of tobacco, and its highly addictive nature is responsible for its widespread use and significant withdrawal effects that result in challenges to smoking cessation therapeutics. Nicotine addiction often begins in adolescence and this is at least partially attributed to the fact that adolescent brain is most susceptible to the neuro-inflammatory effects of nicotine. There is increasing evidence for the involvement of microglial cells, which are the brain's primary homeostatic sensor, in drug dependence and its associated behavioral manifestations particularly in the adolescent brain. A hallmark of neuro-inflammation is microglial activation and activation of microglia by nicotine during adolescent development, which may result in long-term addiction to nicotine. This non-systematic review examines multifactorial etiology of adolescent nicotine addiction, neurobiology of nicotine addiction and the potential mechanisms that underlie the effects of nicotine on inflammatory signaling in the microglia, understanding how nicotine affects the adolescent brain. We speculate, that modulating homeostatic balance in microglia, could have promising therapeutic potential in withdrawal, tolerance, and abstinence-related neural adaptations in nicotine addiction, in the adolescent brain. Further, we discuss nicotine addiction in the context of the sensitization-homeostasis model which provides a theoretical framework for addressing the potential role of microglial homeostasis in neural adaptations underlying nicotine abuse.

Genetic deletion of β-arrestin 2 modulates LSD-stimulated behaviors in mice

Recent evidence suggests that psychedelic drugs can exert beneficial effects on anxiety, depression, and ethanol and nicotine abuse in humans. However, their hallucinogenic side-effects often preclude their clinical use. Lysergic acid diethylamide (LSD) is a prototypical hallucinogen and its psychedelic actions are exerted through the 5-HT2A serotonin receptor (5-HT2AR). 5-HT2AR activation stimulates Gq- and β-arrestin- (βArr) mediated signaling. To separate these signaling modalities, we have used βArr1 and βArr2 mice. We find that LSD stimulates motor activities to similar extents in WT and βArr1-KO mice, with non-significant effects in βArr2-KOs. LSD robustly stimulates many surrogates of psychedelic drug actions including head twitches, grooming, retrograde walking, and nose-poking in WT and βArr1-KO animals. By contrast, LSD slightly stimulates head twitches in βArr2-KO mice, without effects on other surrogates. The 5-HT2AR antagonist MDL100907 (MDL) blocks these LSD effects. LSD also disrupts prepulse inhibition (PPI) in WT and βArr1-KOs; PPI is unaffected in βArr2-KOs. MDL restores PPI in WT mice, but this antagonist is without effect and haloperidol is required in βArr1-KOs. Collectively, these results reveal that LSD’s psychedelic drug-like actions appear to require βArr2.

Executive Functions in Tobacco Use Disorder: New Challenges and Opportunities

There is increasing evidence that executive functions have significative effects on nicotine abuse. An unresolved challenge for smoking cessation interventions is the detection of factors associated with nicotine use. In order to understand how cognition is affected by nicotine abuse, this study was designed to determine the relationship between years of smoking addiction and several variables of executive functions. The sample was composed of 174 smokers, whose age ranged between 27 and 69 years old (M = 47.44; SD = 8.48). Smokers were assessed at baseline with measures of cognitive inhibition [Go/No Go Task and Five Digit Test (FDT)], updating [Visual Search and Attention Test (VSAT) and Letter-Number Sequencing (WAIS IV)] and shifting [Delay Discounting Task (DDT) and Iowa Gambling Task (IGT)] while the outcome measure was years of smoking. The linear regression and correlation analysis highlighting that the variable which has the strongest association with years of smoking is updating. Multivariate analysis of variance (MANCOVA) followed by Tukey post-hoc tests revealed significant differences such that heavy smoking indicated worse performance than light smoking on updating tasks. These findings report the ability of working memory to predict years of smoking and suggest that cigarette packaging warning may experience a loss of effectiveness in heavy smokers.

The Effect of Cardiovascular Comorbidities on Women Compared to Men: Longitudinal Retrospective Analysis (Preprint)

BACKGROUND Although men are more prone to developing cardiovascular disease (CVD) than women, risk factors for CVD, such as nicotine abuse and diabetes mellitus, have been shown to be more detrimental in women than in men. OBJECTIVE We developed a method to systematically investigate population-wide electronic health records for all possible associations between risk factors for CVD and other diagnoses. The developed structured approach allows an exploratory and comprehensive screening of all possible comorbidities of CVD, which are more connected to CVD in either men or women. METHODS Based on a population-wide medical claims dataset comprising 44 million records of inpatient stays in Austria from 2003 to 2014, we determined comorbidities of acute myocardial infarction (AMI; International Classification of Diseases, Tenth Revision [ICD-10] code I21) and chronic ischemic heart disease (CHD; ICD-10 code I25) with a significantly different prevalence in men and women. We introduced a measure of sex difference as a measure of differences in logarithmic odds ratios (ORs) between male and female patients in units of pooled standard errors. RESULTS Except for lipid metabolism disorders (OR for females [ORf]=6.68, 95% confidence interval [CI]=6.57-6.79, OR for males [ORm]=8.31, 95% CI=8.21-8.41), all identified comorbidities were more likely to be associated with AMI and CHD in females than in males: nicotine dependence (ORf=6.16, 95% CI=5.96-6.36, ORm=4.43, 95% CI=4.35-4.5), diabetes mellitus (ORf=3.52, 95% CI=3.45-3.59, ORm=3.13, 95% CI=3.07-3.19), obesity (ORf=3.64, 95% CI=3.56-3.72, ORm=3.33, 95% CI=3.27-3.39), renal disorders (ORf=4.27, 95% CI=4.11-4.44, ORm=3.74, 95% CI=3.67-3.81), asthma (ORf=2.09, 95% CI=1.96-2.23, ORm=1.59, 95% CI=1.5-1.68), and COPD (ORf=2.09, 95% CI 1.96-2.23, ORm=1.59, 95% CI 1.5-1.68). Similar results could be observed for AMI. CONCLUSIONS Although AMI and CHD are more prevalent in men, women appear to be more affected by certain comorbidities of AMI and CHD in their risk for developing CVD.

Modifiable Cardiovascular Risk Factors in Patients With Sporadic Cerebral Cavernous Malformations

Background and Purpose: This study aims to assess the influence of modifiable cardiovascular risk factors on hemorrhage risk of sporadic cerebral cavernous malformations (CCMs). Methods: From 1219 consecutive CCM patients (2003–2018), adult subjects with sporadic CCM and complete magnetic resonance imaging were included. We evaluated presence of intracerebral hemorrhage (ICH) as mode of presentation, occurrence of ICH during follow-up and risk factors arterial hypertension, diabetes, hyperlipidemia, nicotine abuse, and obesity (body mass index >30 kg/m 2 ). Impact of risk factors on ICH at presentation was calculated using univariate and multivariate logistic regression with age and sex adjustment. We performed Kaplan-Meier and Cox regression to analyze cumulative 5-year risk for (re)bleeding. Results: We included 682 patients with CCM. The univariate logistic regression showed a significant relationship (odds ratio=1.938 [95% CI, 1.120–3.353], P =0.018) between obesity and ICH as mode of presentation. Multivariate adjusted logistic regression confirmed significant correlation with odds ratio=1.902 (95% CI, 1.024–3.532, P =0.042). Cox regression did not identify predictors for occurrence of (re)hemorrhage ( P >0.05; hazard ratios: arterial hypertension 1.112 [95% CI, 0.622–1.990], diabetes 0.850 [95% CI, 0.208–3.482], hyperlipidemia 0.719 [95% CI, 0.261–1.981], nicotine abuse 1.123 [95% CI, 0.591–2.134], and obesity 0.928 [95% CI, 0.416–2.070]). Conclusions: This study provides evidence that obesity may be a risk factor for CCM hemorrhage. It was significantly associated with ICH as mode of presentation. Other risk factors (arterial hypertension, diabetes, hyperlipidemia, and current nicotine abuse) showed no such effect. None of the factors showed to be independent predictors for cumulative 5-year risk of (re)bleeding.

LSD’s effects are differentially modulated in arrestin knockout mice

ABSTRACTRecent evidence suggests that psychedelic drugs can exert beneficial effects on anxiety, depression, and ethanol and nicotine abuse in humans. However, the hallucinogenic side-effects of psychedelics often preclude their clinical use. Lysergic acid diethylamide (LSD) is a prototypical hallucinogen and its psychedelic actions are exerted through the 5-HT2A serotonin receptor (5-HT2AR). 5-HT2AR activation stimulates Gq- and β-arrestin-(βArr) mediated signaling. To separate effects of these signaling modes, we have used βArr1 and βArr2 mice. We find that LSD stimulates motor activities to similar extents in WT and βArr1-KO mice, with non-significant effects in βArr2-KOs. LSD robustly stimulates many surrogates of psychedelic drug actions including head twitches, grooming, retrograde walking, and nose poking in WT and βArr1-KO animals. In contrast, LSD only slightly stimulates head twitches in βArr2-KO mice, without effects on retrograde walking or nose poking. The 5-HT2AR antagonist MDL100907 (MDL) blocks these LSD effects. LSD also disrupts prepulse inhibition (PPI) in WT and βArr1-KOs; PPI is unaffected in βArr2-KOs. MDL restores PPI in WT mice, but this antagonist is without effect and haloperidol is required in βArr1-KOs. LSD produces a biphasic body-temperature response in WT mice, a monophasic response in βArr1-KOs, and is without effect in βArr2 mutants. Both MDL and the 5-HT1AR antagonist, WAY 100635 (WAY), block the effects of LSD on body temperatures in WT mice, whereas WAY is effective in βArr1-KOs. Collectively, these results reveal that LSD produces diverse behavioral effects through βArr1 and βArr2, and that LSD’s psychedelic drug-like actions appear to require βArr2.