Balancing Consideration of the Risks and Benefits of E-Cigarettes.

The topic of e-cigarettes is controversial. Opponents focus on e-cigarettes' risks for young people, while supporters emphasize the potential for e-cigarettes to assist smokers in quitting smoking. Most US health organizations, media coverage, and policymakers have focused primarily on risks to youths. Because of their messaging, much of the public-including most smokers-now consider e-cigarette use as dangerous as or more dangerous than smoking. By contrast, the National Academies of Science, Engineering, and Medicine concluded that e-cigarette use is likely far less hazardous than smoking. Policies intended to reduce adolescent vaping may also reduce adult smokers' use of e-cigarettes in quit attempts. Because evidence indicates that e-cigarette use can increase the odds of quitting smoking, many scientists, including this essay's authors, encourage the health community, media, and policymakers to more carefully weigh vaping's potential to reduce adult smoking-attributable mortality. We review the health risks of e-cigarette use, the likelihood that vaping increases smoking cessation, concerns about youth vaping, and the need to balance valid concerns about risks to youths with the potential benefits of increasing adult smoking cessation.

Metabotropic glutamate receptor 5 as a potential target for smoking cessation.

RATIONALE: Most habitual smokers find it difficult to quit smoking because they are dependent upon the nicotine present in tobacco smoke. Tobacco dependence is commonly treated pharmacologically using nicotine replacement therapy or drugs, such as varenicline, that target the nicotinic receptor. Relapse rates, however, remain high, and there remains a need to develop novel non-nicotinic pharmacotherapies for the dependence that are more effective than existing treatments. OBJECTIVE: The purpose of this paper is to review the evidence from preclinical and clinical studies that drugs that antagonise the metabotropic glutamate receptor 5 (mGluR5) in the brain are likely to be efficacious as treatments for tobacco dependence. RESULTS: Imaging studies reveal that chronic exposure to tobacco smoke reduces the density of mGluR5s in human brain. Preclinical results demonstrate that negative allosteric modulators (NAMs) at mGluR5 attenuate both nicotine self-administration and the reinstatement of responding evoked by exposure to conditioned cues paired with nicotine delivery. They also attenuate the effects of nicotine on brain dopamine pathways implicated in addiction. CONCLUSIONS: Although mGluR5 NAMs attenuate most of the key facets of nicotine dependence, they potentiate the symptoms of nicotine withdrawal. This may limit their value as smoking cessation aids. The NAMs that have been employed most widely in preclinical studies of nicotine dependence have too many "off-target" effects to be used clinically. However, newer mGluR5 NAMs have been developed for clinical use in other indications. Future studies will determine if these agents can also be used effectively and safely to treat tobacco dependence.

Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status.

RATIONALE: The diabetes mellitus drug metformin is under investigation in cardiovascular disease, but the molecular mechanisms underlying possible benefits are poorly understood. OBJECTIVE: Here, we have studied anti-inflammatory effects of the drug and their relationship to antihyperglycemic properties. METHODS AND RESULTS: In primary hepatocytes from healthy animals, metformin and the IKKß (inhibitor of kappa B kinase) inhibitor BI605906 both inhibited tumor necrosis factor-α-dependent IκB degradation and expression of proinflammatory mediators interleukin-6, interleukin-1ß, and CXCL1/2 (C-X-C motif ligand 1/2). Metformin suppressed IKKα/ß activation, an effect that could be separated from some metabolic actions, in that BI605906 did not mimic effects of metformin on lipogenic gene expression, glucose production, and AMP-activated protein kinase activation. Equally AMP-activated protein kinase was not required either for mitochondrial suppression of IκB degradation. Consistent with discrete anti-inflammatory actions, in macrophages, metformin specifically blunted secretion of proinflammatory cytokines, without inhibiting M1/M2 differentiation or activation. In a large treatment naive diabetes mellitus population cohort, we observed differences in the systemic inflammation marker, neutrophil to lymphocyte ratio, after incident treatment with either metformin or sulfonylurea monotherapy. Compared with sulfonylurea exposure, metformin reduced the mean log-transformed neutrophil to lymphocyte ratio after 8 to 16 months by 0.09 U (95% confidence interval, 0.02-0.17; P=0.013) and increased the likelihood that neutrophil to lymphocyte ratio would be lower than baseline after 8 to 16 months (odds ratio, 1.83; 95% confidence interval, 1.22-2.75; P=0.00364). Following up these findings in a double-blind placebo controlled trial in nondiabetic heart failure (trial registration: NCT00473876), metformin suppressed plasma cytokines including the aging-associated cytokine CCL11 (C-C motif chemokine ligand 11). CONCLUSION: We conclude that anti-inflammatory properties of metformin are exerted irrespective of diabetes mellitus status. This may accelerate investigation of drug utility in nondiabetic cardiovascular disease groups. CLINICAL TRIAL REGISTRATION: Name of the trial registry: TAYSIDE trial (Metformin in Insulin Resistant Left Ventricular [LV] Dysfunction). URL: https://www.clinicaltrials.gov. Unique identifier: NCT00473876.

The role of mesoaccumbens dopamine in nicotine dependence.

There is abundant evidence that the dopamine (DA) neurons that project to the nucleus accumbens play a central role in neurobiological mechanisms underpinning drug dependence. This chapter considers the ways in which these projections facilitate the addiction to nicotine and tobacco. It focuses on the complimentary roles of the two principal subdivisions of the nucleus accumbens, the accumbal core and shell, in the acquisition and maintenance of nicotine-seeking behavior. The ways in which tonic and phasic firing of the neurons contributes to the ways in which the accumbens mediate the behavioral responses to nicotine are also considered. Experimental studies suggest that nicotine has relatively weak addictive properties which are insufficient to explain the powerful addictive properties of tobacco smoke. This chapter discusses hypotheses that seek to explain this conundrum. They implicate both discrete sensory stimuli closely paired with the delivery of tobacco smoke and contextual stimuli habitually associated with the delivery of the drug. The mechanisms by which each type of stimulus influence tobacco dependence are hypothesized to depend upon the increased DA release and overflow, respectively, in the two subdivisions of the accumbens. It is suggested that a majority of pharmacotherapies for tobacco dependence are not more successful because they fail to address this important aspect of the dependence.

High fat feeding is associated with stimulation of the hypothalamic-pituitary-adrenal axis and reduced anxiety in the rat.

Previous studies have shown that diet-induced obesity is associated with insulin resistance and impaired feedback control of the hypothalamic-pituitary-adrenal (HPA) axis. The objective of this study was to test the hypothesis that hyper-secretion of glucocorticoid, evoked by feeding rats a high fat (HF) diet for 12 weeks, also influences behavioural and neural responses to the elevated plus-maze (EPM) test of anxiety. HF-fed animals exhibited anxiolytic-like behaviour in the EPM but were also hyperactive in this test. Covariant analysis established that the anxiolytic-like behaviour was not secondary to the increase in activity. The HF diet significantly increased basal levels of plasma corticosterone. The groups exposed to the EPM also displayed increased plasma corticosterone levels compared to the relevant control group, although the increment was smaller in the HF-fed animals. Glucocorticoid receptor (GR) immunoreactivity in the cytoplasmic fraction of parietal cortex and hypothalamus and the particulate fraction of the parietal cortex were increased by HF feeding. The behavioural changes evoked by HF feeding did not correlate significantly with changes in GR immunoreactivity in each treatment group or 5-HT turnover in the brain areas studied. It is concluded that anxiolytic properties evoked in the EPM by high fat feeding are unlikely to be related to the changes in HPA function seen in animals fed this diet.

Extrasynaptic glycine receptors of rodent dorsal raphe serotonergic neurons: a sensitive target for ethanol.

Alcohol abuse is a significant medical and social problem. Several neurotransmitter systems are implicated in ethanol's actions, with certain receptors and ion channels emerging as putative targets. The dorsal raphe (DR) nucleus is associated with the behavioral actions of alcohol, but ethanol actions on these neurons are not well understood. Here, using immunohistochemistry and electrophysiology we characterize DR inhibitory transmission and its sensitivity to ethanol. DR neurons exhibit inhibitory 'phasic' post-synaptic currents mediated primarily by synaptic GABAA receptors (GABAAR) and, to a lesser extent, by synaptic glycine receptors (GlyR). In addition to such phasic transmission mediated by the vesicular release of neurotransmitter, the activity of certain neurons may be governed by a 'tonic' conductance resulting from ambient GABA activating extrasynaptic GABAARs. However, for DR neurons extrasynaptic GABAARs exert only a limited influence. By contrast, we report that unusually the GlyR antagonist strychnine reveals a large tonic conductance mediated by extrasynaptic GlyRs, which dominates DR inhibition. In agreement, for DR neurons strychnine increases their input resistance, induces membrane depolarization, and consequently augments their excitability. Importantly, this glycinergic conductance is greatly enhanced in a strychnine-sensitive fashion, by behaviorally relevant ethanol concentrations, by drugs used for the treatment of alcohol withdrawal, and by taurine, an ingredient of certain 'energy drinks' often imbibed with ethanol. These findings identify extrasynaptic GlyRs as critical regulators of DR excitability and a novel molecular target for ethanol.

Nicotine modifies in vivo and in vitro rat hippocampal amyloid precursor protein processing in young but not old rats.

Previous studies have shown that administration of nicotine modifies the expression and secretion of amyloid precursor protein (APP) in various cell lines. The present study investigated the extent to which chronic subcutaneous nicotine administration influences APP levels and processing in cerebral cortex, striatum and hippocampus of young and old rat brains. The results showed that constant nicotine infusion (0.25 or 4.00mg/kg/day) increased the levels of particulate APP (APPp) but not secreted APP (APPs) in the hippocampus of young rats in vivo. This response to nicotine was not observed in the striatum or cerebral cortex of young rats or in any of the brain regions examined in old animals. Subsequent in vitro analysis demonstrated that nicotine enhanced the release of APPs from hippocampal slice preparations and that this increase was attenuated by mecamylamine, a non-selective nicotinic acetylcholine receptor (nAChR) antagonist. The in vitro effect of nicotine on APPs was age-related, being only detected from hippocampal slices derived from the young but not the older animals. These results suggest that nicotine modulates APP expression and secretion in the hippocampus and that the responses observed to the drug are age-dependent being only detected in younger rats.

Historical and current perspective on tobacco use and nicotine addiction.

Although the addictive influence of tobacco was recognized very early, the modern concepts of nicotine addiction have relied on knowledge of cholinergic neurotransmission and nicotinic acetylcholine receptors (nAChRs). The discovery of the 'receptive substance' by Langley, that would turn out to be nAChRs, and 'Vagusstoff' (acetylcholine) by Loewi, coincided with an exciting time when the concept of chemical synaptic transmission was being formulated. More recently, the application of more powerful techniques and the study of animal models that replicate key features of nicotine dependence have led to important advancements in our understanding of molecular, cellular and systems mechanisms of nicotine addiction. In this review, we present a historical perspective and overview of the research that has led to our present understanding of nicotine addiction.

The effects of the mGluR5 receptor antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) on the stimulation of dopamine release evoked by nicotine in the rat brain.

Previous studies have shown that the prior administration of metabotropic glutamate receptor 5 (MGluR5) receptor antagonists inhibit responding for nicotine in an intravenous self-administration experiment. However, recent studies in this laboratory have shown that an mGluR5 receptor antagonist, MPEP (2-methyl-6-(phenylethynyl)-pyridine), also attenuates contextually-conditioned responding evoked by cues associated with the delivery or availability of nicotine. Thus, the results to date do not provide unequivocal evidence that the effects of mGluR5 receptor antagonists on responding for nicotine reflect a direct functional interaction between the antagonists and nicotine per se. This study employed in vivo microdialysis to test the hypothesis that the prior administration of the mGluR5 receptor antagonist, MPEP, inhibits a neural response to nicotine, increased dopamine (DA) overflow in the nucleus accumbens, implicated in directly in nicotine reinforcement. The results confirmed that prior administration of MPEP (2.5 mg/kg and 5 mg/kg IP) dose-dependently reduced responding for nicotine in a self-administration experiment. The higher dose caused complete inhibition of responding in a majority of the animals tested. MPEP injections, over the same dose range, also inhibited the effects of nicotine on DA overflow in the shell and core subdivisions of the rat nucleus accumbens. It is concluded that the data support the hypothesis that, in addition to their putative role in contextually-conditioned responding for nicotine, mGluR5 receptors are also implicated the primary reinforcing properties of the drug which depend upon increased DA overflow in the nucleus accumbens.

High fat feeding promotes simultaneous decline in insulin sensitivity and cognitive performance in a delayed matching and non-matching to position task.

Obesity is the single greatest risk factor for the development of Type 2 diabetes mellitus (T2DM), with the prevalence of both dramatically increasing in recent years. These conditions are associated with medical complications such as hypertension, neuropathy and cardiovascular disease. Recent evidence also suggests a greater risk of developing dementia including Alzheimer's disease. The molecular mechanisms governing these changes remain obscure, although epidemiological evidence suggests that reduced insulin sensitivity (a characteristic of T2DM) is an independent risk factor for Alzheimer's disease. Here we examine the effects of diet-induced insulin resistance on cognitive ability in an animal model not predisposed to develop Alzheimer's pathology. Following 12 weeks on a high fat diet (45% of calories as crude fat) male Wistar rats were overweight and insulin resistant but not frankly diabetic. High fat fed animals were consistently poorer in all aspects of an operant based delayed matching to position task, yet were not impaired in spatial working memory as judged by the open field watermaze test. The cognitive deficit of the HF fed animals was most apparent when the task was switched from matching to non-matching to position, suggestive of an inability to change contingency. Performance in this task was negatively correlated with whole body insulin sensitivity but not weight gain. In conclusion this study has shown that insulin resistant animals exhibit impairments in an operant measure of behavioural flexibility which precede the development of diabetes.

The effects of the mGluR5 receptor antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP) on behavioural responses to nicotine.

RATIONALE: Previous studies have shown that blockade of metabotropic glutamate 5 receptors (mGluR5) results in inhibition of nicotine self-administration in experimental animals. However, these studies have not established the behavioural mechanisms which mediate these effects or the extent to which the effects of mGluR5 antagonism on nicotine self-administration reflect a selective attenuation of nicotine reinforcement. OBJECTIVES: To investigate the effects of antagonising mGluR5 receptors on psychopharmacological responses to nicotine measured using conditioned and unconditioned behaviours. RESULTS: 2-Methyl-6-(phenylethynyl)-pyridine (MPEP) significantly (P < 0.01) reduced nicotine self-administration and attenuated (P < 0.01) the ability of non-contingent nicotine to enhance the reinforcing properties of a weak reinforcer (extinguishing the house light in an operant chamber). It also attenuated (P < 0.05) the much lower levels of responding for this reinforcer measured in control animals treated with saline. MPEP did not attenuate the increase in locomotor activity induced by acute and repeated nicotine in animals habituated on the test day to the test environment. Furthermore, it had no significant effects on responding for a palatable food reward. By contrast, MPEP significantly reduced (P < 0.001) conditioned locomotor stimulation evoked by pairing nicotine with a specific environment. CONCLUSION: The results are consistent with the hypothesis that mGluR5 receptors play an important role in mediating the effects of contextual cues in conditioned behavioural responses to nicotine.

Inhibition of thalamic excitability by 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol: a selective role for delta-GABA(A) receptors.

The sedative and hypnotic agent 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol (THIP) is a GABA(A) receptor (GABA(A)R) agonist that preferentially activates delta-subunit-containing GABA(A)Rs (delta-GABA(A)Rs). To clarify the role of delta-GABA(A)Rs in mediating the sedative actions of THIP, we utilized mice lacking the alpha(1)- or delta-subunit in a combined electrophysiological and behavioural analysis. Whole-cell patch-clamp recordings were obtained from ventrobasal thalamic nucleus (VB) neurones at a holding potential of -60 mV. Application of bicuculline to wild-type (WT) VB neurones revealed a GABA(A)R-mediated tonic current of 92 +/- 19 pA, which was greatly reduced (13 +/- 5 pA) for VB neurones of delta(0/0) mice. Deletion of the delta- but not the alpha(1)-subunit dramatically reduced the THIP (1 mum)-induced inward current in these neurones (WT, -309 +/- 23 pA; delta(0/0), -18 +/- 3 pA; alpha(1) (0/0), -377 +/- 45 pA). Furthermore, THIP selectively decreased the excitability of WT and alpha(1) (0/0) but not delta(0/0) VB neurones. THIP did not affect the properties of miniature inhibitory post-synaptic currents in any of the genotypes. No differences in rotarod performance and locomotor activity were observed across the three genotypes. In WT mice, performance of these behaviours was impaired by THIP in a dose-dependent manner. The effect of THIP on rotarod performance was blunted for delta(0/0) but not alpha(1) (0/0) mice. We previously reported that deletion of the alpha(1)-subunit abolished synaptic GABA(A) responses of VB neurones. Therefore, collectively, these findings suggest that extrasynaptic delta-GABA(A)Rs vs. synaptic alpha(1)-subunit-containing GABA(A)Rs of thalamocortical neurones represent an important molecular target underpinning the sedative actions of THIP.

The neuronal pathways mediating the behavioral and addictive properties of nicotine.

This chapter considers the neurobiological mechanisms that are thought to mediate the reinforcing or rewarding properties of nicotine. It focuses on the data (derived principally from studies with experimental animals) showing that nicotine, like other drugs of dependence, stimulates the mesolimbic dopamine (DA) neurones that project to the nucleus accumbens and that these effects play a pivotal role in the biology underlying nicotine dependence. The reinforcing or rewarding properties of nicotine are thought to be associated particularly with the increase in DA overflow evoked in the shell subdivision of the accumbens. However, behavioural studies suggest that these properties of nicotine in experimental animals do not seem to be sufficiently potent to explain the powerful addiction to tobacco experienced by most habitual smokers. This chapter also considers the biological mechanisms that mediate the effects of cues and stimuli associated with the presentation of nicotine, which are thought to contribute significantly to the powerful addictive properties of tobacco smoke.

Chronic bupropion differentially alters the reinforcing, reward-enhancing and conditioned motivational properties of nicotine in rats.

Bupropion is an effective anti-smoking agent in humans, but the behavioral mechanisms mediating this effect are unclear. The present studies assessed the effects of chronic bupropion on the reinforcing and reward-enhancing effects of self-administered nicotine, and on the motivational properties of a nicotine-associated conditioned reinforcer. The present studies also assessed the reward-enhancing effects of nicotine self-administration under different levels of access to nicotine, and the effects of enforced abstinence from self-administered nicotine on brain reward function and somatic signs. Rats were prepared with bipolar electrodes in the lateral hypothalamus and trained on a discrete trial intracranial self-stimulation (ICSS) task. After establishing stable ICSS thresholds, rats were prepared with intravenous catheters and allowed to self-administer nicotine at different levels of access. Self-administered nicotine lowered ICSS thresholds, thereby providing a measure of the reward-enhancing effects of nicotine. Abstinence from 6h/d 7d/wk nicotine self-administration was associated with increased somatic signs of nicotine withdrawal and unchanged brain reward thresholds. Chronic bupropion administration via subcutaneous osmotic minipump had no effect on nicotine self-administration, but attenuated nicotine-induced enhancement of brain reward function and enhanced the motivational properties of a previously nicotine-associated conditioned stimulus. Thus, it is unlikely that chronic bupropion exerts anti-smoking effects by attenuating the primary or conditioned reinforcing effects of nicotine. Rather, preclinical investigations suggest that bupropion attenuates nicotine-induced enhancement of brain reward function and reverses the anhedonic, somatic, and neurochemical correlates of nicotine withdrawal.

The effect of stress on the expression of the amyloid precursor protein in rat brain.

The abnormal processing of the amyloid precursor protein (APP) is a pivotal event in the development of the unique pathology that defines Alzheimer's disease (AD). Stress, and the associated increase in corticosteroids, appear to accelerate brain ageing and may increase vulnerability to Alzheimer's disease via altered APP processing. In this study, rats were repeatedly exposed to an unavoidable stressor, an open elevated platform. Previous studies in this laboratory have shown that a single exposure produces a marked increase in plasma corticosterone levels but animals develop tolerance to this effect between 10 and 20 daily sessions. Twenty-four hours after stress, there was an increase in the ratio of the deglycosylated form of APP in the particulate fraction of the brain, which subsequently habituated after 20 days. The levels of soluble APP (APPs) tended to be lower in the stress groups compared to controls except for a significant increase in the hippocampus after 20 days of platform exposure. Since APPs is reported to have neurotrophic properties, this increased release may represent a neuroprotective response to repeated stress. It is possible that the ability to mount this response decreases with age thus increasing the vulnerability to stress-induced AD-related pathology.

Neuropharmacology and potential efficacy of new treatments for tobacco dependence.

This review considers some of the novel therapies that are under development for the treatment of tobacco dependence, outlines their efficacy in clinical studies and explains their mechanisms of action in terms of contemporary theories for the psychobiology of the dependence. It focuses on three treatments with differing mechanisms of action that are at different stages of clinical development. The first is varenicline, a partial agonist at the alpha4beta2 nicotinic receptors, which are thought to play a central role in the addiction to nicotine. Preclinically, this drug mimics the effects of nicotine on dopamine (DA) release in the nucleus accumbens when given alone but attenuates this response to a subsequent nicotine challenge and reduces nicotine self administration. Very encouraging results have been seen in the five clinical studies that have been reported with this drug. The second compound, rimonabant, is a cannabinoid CB1 receptor antagonist. Preclinically, this compound reduces nicotine self administration, DA turnover in nucleus accumbens and attenuates reinstatement of nicotine-seeking behaviour. Clinically, the drug is well tolerated but its effects on smoking cessation are equivocal. However, it has the valuable additional property of inhibiting post-cessation weight gain. Nicotine 'vaccines' are the final group of treatments considered, which involves raising antibodies in the blood that limit the amount of nicotine that penetrates into the brain, thereby reducing the psychopharmacological responses to the drug. The vaccines also reduce DA turnover in nucleus accumbens and reinstatement of nicotine-seeking behaviour after nicotine readministration. The three vaccines discussed are well tolerated and show signs of good efficacy; however, the increase in antibody titre, evoked by the treatment, shows significant inter-individual variation and is generally short lived. Thus, although this approach may provide a valuable aid to smoking cessation, it seems unlikely that it can be used for primary prevention.