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    New mechanisms and perspectives in nicotine withdrawal. Jackson K J,Muldoon P P,De Biasi M,Damaj M I Neuropharmacology Diseases associated with tobacco use constitute a major health problem worldwide. Upon cessation of tobacco use, an unpleasant withdrawal syndrome occurs in dependent individuals. Avoidance of the negative state produced by nicotine withdrawal represents a motivational component that promotes continued tobacco use and relapse after smoking cessation. With the modest success rate of currently available smoking cessation therapies, understanding mechanisms involved in the nicotine withdrawal syndrome are crucial for developing successful treatments. Animal models provide a useful tool for examining neuroadaptative mechanisms and factors influencing nicotine withdrawal, including sex, age, and genetic factors. Such research has also identified an important role for nicotinic receptor subtypes in different aspects of the nicotine withdrawal syndrome (e.g., physical vs. affective signs). In addition to nicotinic receptors, the opioid and endocannabinoid systems, various signal transduction pathways, neurotransmitters, and neuropeptides have been implicated in the nicotine withdrawal syndrome. Animal studies have informed human studies of genetic variants and potential targets for smoking cessation therapies. Overall, the available literature indicates that the nicotine withdrawal syndrome is complex, and involves a range of neurobiological mechanisms. As research in nicotine withdrawal progresses, new pharmacological options for smokers attempting to quit can be identified, and treatments with fewer side effects that are better tailored to the unique characteristics of patients may become available. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. 10.1016/j.neuropharm.2014.11.009
    Nicotinic Mechanisms Modulate Ethanol Withdrawal and Modify Time Course and Symptoms Severity of Simultaneous Withdrawal from Alcohol and Nicotine. Perez Erika,Quijano-Cardé Natalia,De Biasi Mariella Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Alcohol and nicotine are among the top causes of preventable death in the United States. Unfortunately, people who are dependent on alcohol are more likely to smoke than individuals in the general population. Similarly, smokers are more likely to abuse alcohol. Alcohol and nicotine codependence affects health in many ways and leads to poorer treatment outcomes in subjects who want to quit. This study examined the interaction of alcohol and nicotine during withdrawal and compared abstinence symptoms during withdrawal from one of the two drugs only vs both. Our results indicate that simultaneous withdrawal from alcohol and nicotine produces physical symptoms that are more severe and last longer than those experienced during withdrawal from one of the two drugs alone. In animals experiencing withdrawal after chronic ethanol treatment, acute nicotine exposure was sufficient to prevent abstinence symptoms. Similarly, symptoms were prevented when alcohol was injected acutely in mice undergoing nicotine withdrawal. These experiments provide evidence for the involvement of the nicotinic cholinergic system in alcohol withdrawal. Furthermore, the outcomes of intracranial microinfusions of mecamylamine, a nonselective nicotinic receptor antagonist, highlight a major role for the nicotinic receptors expressed in medial habenula and interpeduncular nucleus during withdrawal. Overall, the data support the notion that modulating the nicotinic cholinergic system might help to maintain long-term abstinence from alcohol. 10.1038/npp.2015.80
    Reduction of anxiety sensitivity in relation to nicotine withdrawal symptoms during smoking cessation: an examination among successful quitters. Bakhshaie Jafar,Zvolensky Michael J,Langdon Kirsten J,Leventhal Adam M,Schmidt Norman B Cognitive behaviour therapy Anxiety sensitivity has been implicated as a potential risk factor for post-quit withdrawal symptoms. The present study examined relations between the extent of change in anxiety sensitivity and the course of nicotine withdrawal symptoms experienced during the initial two weeks of a quit attempt among treatment-seeking smokers. The sample consisted of 29 adult daily smokers (34% female; M = 47.7, SD = 13.1) who successfully quit and maintained their abstinence. After adjusting for the effects of gender, treatment condition, use of nicotine replacement therapy, nicotine dependence, alcohol use problems, baseline levels of anxiety sensitivity, and reductions in negative affect, greater reductions in anxiety sensitivity were related to faster decreases in withdrawal symptoms. The current data suggest that there may be merit to employ anxiety sensitivity reduction methods for the management of emergent withdrawal symptoms in smoking cessation treatment. 10.1080/16506073.2017.1395907
    Sex differences in tobacco withdrawal and responses to smoking reduced-nicotine cigarettes in young smokers. Faulkner Paul,Petersen Nicole,Ghahremani Dara G,Cox Chelsea M,Tyndale Rachel F,Hellemann Gerhard S,London Edythe D Psychopharmacology RATIONALE:Policies that establish a standard for reduced nicotine content in cigarettes can decrease the prevalence of smoking in the USA. Cigarettes with nicotine yields as low as 0.05 mg produce substantial occupancy of nicotinic acetylcholine receptors (26%), but women and men respond differently to these cigarettes. OBJECTIVE:This study aimed to measure responses to smoking cigarettes that varied widely in nicotine yields, investigating whether sex differences in the effects on craving, withdrawal, and affect would be observed at even lower nicotine yields than previously studied, and in young smokers. METHODS:Overnight abstinent young smokers (23 men, 23 women, mean age 22.18) provided self-reports of craving, withdrawal, and affect before and after smoking cigarettes with yields of 0.027, 0.110, 0.231, or 0.763 mg nicotine, and evaluated characteristics of each cigarette. RESULTS:Compared to abstinent young men, abstinent young women reported greater negative affect, psychological withdrawal, and sedation, all of which were relieved equally by all cigarettes. Men but not women reported greater craving reduction, perceived nicotine content, and cigarette liking with increasing nicotine dose. CONCLUSIONS:Men may experience less smoking-related relief of craving, and enjoy cigarettes less, if nicotine yields are reduced to very low levels. Conversely, women respond equally well to cigarettes with nicotine yields as low as 0.027 mg as to cigarettes with nicotine yields 28-fold higher (0.763 mg). These differences are relevant for policy regarding reduced nicotine in cigarettes and may influence the efficacy and acceptability of reduced-nicotine cigarettes as smoking cessation aids. 10.1007/s00213-017-4755-x
    Progressive modulation of accumbal neurotransmission and anxiety-like behavior following protracted nicotine withdrawal. Morud Julia,Strandberg Joakim,Andrén Anna,Ericson Mia,Söderpalm Bo,Adermark Louise Neuropharmacology Due to the highly addictive properties of nicotine, a low percentage of users successfully maintain cessation for longer periods of time. This might be linked to neuroadaptations elicited by the drug, and understanding progressive changes in neuronal function might provide critical insight into nicotine addiction. We have previously shown that neurotransmission in the nucleus accumbens (nAc), a key brain region with respect to drug reinforcement and relapse, is suppressed for as long as seven months after a brief period of nicotine treatment. Studies were therefore performed to define the temporal properties of these effects, and to assess behavioral correlates to altered neurotransmission. Ex vivo electrophysiology revealed progressive depression of synaptic efficacy in the nAc of rats previously receiving nicotine. In addition, following three months of nicotine withdrawal, the responses to GABA receptor modulating drugs were blunted together with downregulation of several GABA receptor subunits. In correlation to reduced accumbal neurotransmission, a reduced anxiety-like behavior; assessed in the elevated plus-maze and marble burying tests, were identified in animals pre-treated with nicotine. Lastly, to test the causal relationship between suppressed excitability in the nAc and reduced anxiety-like behavior, rats received local administration of diazepam in the nAc while monitoring behavioral effects on the elevated plus-maze. These results show that nicotine produces long-lasting changes in the GABAergic system, which are observed first after extended withdrawal. Our data also suggest that nicotine produces a progressive suppression of accumbal excitability, which could result in behavioral alterations that may have implications for further drug intake. 10.1016/j.neuropharm.2017.10.002
    Adolescents and adults differ in the immediate and long-term impact of nicotine administration and withdrawal on cardiac norepinephrine. Slotkin Theodore A,Stadler Ashley,Skavicus Samantha,Seidler Frederic J Brain research bulletin Cardiovascular responses to smoking cessation may differ in adolescents compared to adults. We administered nicotine by osmotic minipump infusion for 17 days to adolescent and adult rats (30 and 90 days of age, respectively) and examined cardiac norepinephrine levels during treatment, after withdrawal, and for months after cessation. In adults, nicotine evoked a significant elevation of cardiac norepinephrine and a distinct spike upon withdrawal, after which the levels returned to normal; the effect was specific to males. In contrast, adolescents did not show significant changes during nicotine treatment or in the immediate post-withdrawal period. However, beginning in young adulthood, males exposed to adolescent nicotine showed sustained elevations of cardiac norepinephrine, followed by later-emerging deficits that persisted through six months of age. We then conducted adolescent exposure using twice-daily injections, a regimen that augments stress associated with inter-dose withdrawal episodes. With the injection route, adolescents showed an enhanced cardiac norepinephrine response, reinforcing the relationship between withdrawal stress and a surge in cardiac norepinephrine levels. The relative resistance of adolescents to the acute nicotine withdrawal response is likely to make episodic nicotine exposure less stressful or aversive than in adults. Equally important, the long-term changes after adolescent nicotine exposure resemble those known to be associated with risk of hypertension in young adulthood (elevated norepinephrine) or subsequent congestive heart disease (norepinephrine deficits). Our findings reinforce the unique responses and consequences of nicotine exposure in adolescence, the period in which most smokers commence tobacco use. 10.1016/j.brainresbull.2016.03.006
    [Health Effects Accompanying the Transition from Cigarettes to Heat-not-burn Tobacco: Nicotine Dependence, Nicotine Withdrawal Symptoms, and Changes in Smoking Behaviors]. Kawamura Kosuke,Yamada Kazuko,Morioka Ikuharu Nihon eiseigaku zasshi. Japanese journal of hygiene OBJECTIVES:The purposes of this research were to investigate the hazardous effects of heat-not-burn tobacco and to clarify the health effects accompanying the transition from cigarettes to heat-not-burn tobacco. METHODS:The concentrations of carbon monoxide, ammonia, formaldehyde, acetaldehyde, and dust (hazardous substances) were measured in the smoke of heat-not-burn tobacco. Twenty-nine smokers were used as the subjects. The concentrations of hazardous substances were measured in exhalation of heat-not-burn tobacco. The concentration of cotinine in saliva was also measured after the transition. A questionnaire survey was performed before and after the transition to evaluate nicotine dependence, nicotine withdrawal symptoms, and smoking behaviors. RESULTS:In the mainstream smoke, all hazardous substances investigated were detected. Carbon monoxide and dust were detected in the exhalation of heat-not-burn tobacco. The concentration of cotinine in the saliva of heat-not-burn tobacco users corresponded to that of cigarette smokers. Cigarette smoking was significantly positively related to the score of Fagerström Test for Nicotine Dependence (FTND). Heat-not-burn tobacco was significantly positively related to FTND and Minnesota Nicotine Withdrawal Scale (MNWS) scores. The group in which the number of heat-not-burn tobacco sticks consumed increased after transition showed a smaller number of cigarettes consumed and a higher MNWS score before transition than the group in which it decreased after transition. These two factors were significantly related to the difference between the numbers of cigarettes and heat-not-burn tobacco sticks in multiple linear regression analysis. CONCLUSIONS:The mainstream smoke of heat-not-burn tobacco contains harmful substances. There were the possibilities that nicotine dependence and nicotine withdrawal symptoms appear after transition and that the number of heat-not-burn tobacco sticks consumed increases. 10.1265/jjh.73.379
    CB Cannabinoid Receptors Mediate Cognitive Deficits and Structural Plasticity Changes During Nicotine Withdrawal. Saravia Rocio,Flores África,Plaza-Zabala Ainhoa,Busquets-Garcia Arnau,Pastor Antoni,de la Torre Rafael,Di Marzo Vincenzo,Marsicano Giovanni,Ozaita Andrés,Maldonado Rafael,Berrendero Fernando Biological psychiatry BACKGROUND:Tobacco withdrawal is associated with deficits in cognitive function, including attention, working memory, and episodic memory. Understanding the neurobiological mechanisms involved in these effects is crucial because cognitive deficits during nicotine withdrawal may predict relapse in humans. METHODS:We investigated in mice the role of CB cannabinoid receptors (CBRs) in memory impairment and spine density changes induced by nicotine withdrawal precipitated by the nicotinic antagonist mecamylamine. Drugs acting on the endocannabinoid system and genetically modified mice were used. RESULTS:Memory impairment during nicotine withdrawal was blocked by the CBR antagonist rimonabant or the genetic deletion of CBR in forebrain gamma-aminobutyric acidergic (GABAergic) neurons (GABA-CBR). An increase of 2-arachidonoylglycerol (2-AG), but not anandamide, was observed during nicotine withdrawal. The selective inhibitor of 2-AG biosynthesis O7460 abolished cognitive deficits of nicotine abstinence, whereas the inhibitor of 2-AG enzymatic degradation JZL184 did not produce any effect in cognitive impairment. Moreover, memory impairment was prevented by the selective mammalian target of rapamycin inhibitor temsirolimus and the protein synthesis inhibitor anisomycin. Mature dendritic spines on CA1 pyramidal hippocampal neurons decreased 4 days after the precipitation of nicotine withdrawal, when the cognitive deficits were still present. Indeed, a correlation between memory performance and mature spine density was found. Interestingly, these structural plasticity alterations were normalized in GABA-CBR conditional knockout mice and after subchronic treatment with rimonabant. CONCLUSIONS:These findings underline the interest of CBR as a target to improve cognitive performance during early nicotine withdrawal. Cognitive deficits in early abstinence are associated with increased relapse risk. 10.1016/j.biopsych.2016.07.007
    Adolescent smokers' response to reducing the nicotine content of cigarettes: Acute effects on withdrawal symptoms and subjective evaluations. Cassidy Rachel N,Colby Suzanne M,Tidey Jennifer W,Jackson Kristina M,Cioe Patricia A,Krishnan-Sarin Suchitra,Hatsukami Dorothy Drug and alcohol dependence BACKGROUND:Mandating a reduction in the nicotine content of cigarettes to a minimally addictive level could dramatically reduce smoking rates in the US. However, little is known about the effects of reduced nicotine content cigarettes in adolescents. METHODS:Following overnight abstinence, adolescent daily smokers (ages 15-19, n = 50) reported on their craving, withdrawal, and positive and negative affect pre- and post- ad lib smoking of one cigarette containing varying nicotine content (15.8, 5.2, 1.3 and 0.4 mg/g of tobacco) in the laboratory and reported their subjective evaluations of each cigarette. Carbon monoxide (CO) boost from pre- to post-cigarette was calculated to determine if lower-nicotine cigarettes led to differential acute changes in toxicant exposure. RESULTS:All four nicotine cigarette types significantly reduced abstinence-induced craving, withdrawal, and negative affect (all p's < .05). Mixed models evaluating the effect of nicotine content, with nicotine dependence level and gender included as covariates, revealed a significant effect of nicotine content on craving and subjective evaluations: higher nicotine content resulted in greater reductions in craving and increases in both positive and negative subjective evaluations. There were no significant effects of nicotine dose on withdrawal symptoms, negative affect, or CO boost. CONCLUSIONS:These results suggest that lower nicotine cigarettes might result in reduced abuse liability compared to higher nicotine content cigarettes due to reduced positive subjective effects, while still reducing withdrawal, in adolescents. These results highlight the potential feasibility of this policy approach and support continued research on how a nicotine reduction policy may affect adolescent smoking patterns. 10.1016/j.drugalcdep.2018.04.006
    Effects of Nicotine Metabolic Rate on Withdrawal Symptoms and Response to Cigarette Smoking After Abstinence. Liakoni Evangelia,Edwards Kathryn C,St Helen Gideon,Nardone Natalie,Dempsey Delia A,Tyndale Rachel F,Benowitz Neal L Clinical pharmacology and therapeutics This study investigated the influence of the rate of nicotine metabolism, as indicated by the nicotine metabolite ratio (NMR), on tobacco dependence. We stratified 136 smokers on the basis of saliva NMR as fast (n = 65) and slow (n = 71) metabolizers. Two "loading cigarettes" were smoked after overnight, and a "reward cigarette" was smoked after 6 hours of daytime, abstinence. Blood nicotine concentrations, expired carbon monoxide, withdrawal/craving, and reward questionnaires were collected before/after smoking and during daytime abstinence. Compared with slow metabolizers, fast metabolizers had a shorter nicotine elimination half-life (P < 0.001), lower plasma nicotine concentrations (P < 0.001), and higher withdrawal/craving scores (P < 0.05) for most times during daytime abstinence, indicating that fast metabolizers are likely smoking more to relieve withdrawal symptoms (negative reinforcement). Reward/satisfaction scores were similar in fast and slow metabolizers, suggesting that faster nicotine metabolism, assessed by NMR, is not associated with greater positive reinforcement. CYP2A6 normal (n = 82) and reduced (n = 42) genotype predicted plasma nicotine concentrations but not withdrawal symptoms. 10.1002/cpt.1238
    Effects of reduced nicotine content cigarettes on individual withdrawal symptoms over time and during abstinence. Dermody Sarah S,McClernon F Joseph,Benowitz Neal,Luo Xianghua,Tidey Jennifer W,Smith Tracy T,Vandrey Ryan,Hatsukami Dorothy,Donny Eric C Experimental and clinical psychopharmacology In the United States, the Food and Drug Administration (FDA) has initiated a public dialogue about reducing the nicotine content of cigarettes. A reduced-nicotine standard could increase withdrawal symptoms among current smokers. We examined the impact of switching smokers to cigarettes that varied in nicotine content on withdrawal symptoms over 6 weeks. A secondary analysis (N = 839) of a 10-site, double-blind clinical trial of nontreatment-seeking smokers was completed. Participants were instructed to smoke study cigarettes, containing 0.4 to 15.8 mg of nicotine/g of tobacco, for 6 weeks and were then abstinent overnight. Using latent growth curves, trajectories of individual withdrawal symptoms were compared between the reduced nicotine content (RNC) conditions and a normal nicotine content (NNC) condition. Path analyses compared symptoms after overnight abstinence. Relative to NNC cigarettes, participants smoking RNC cigarettes had increased anger/irritability/frustration and increased appetite/weight gain during the initial weeks, but the symptoms resolved by Week 6. Individuals who were biochemically verified as adherent with using only the 0.4 mg/g cigarettes had higher sadness levels (Cohen's d = .40) at Week 6 compared with the NNC condition, although symptoms were mild. After a post-Week 6 overnight abstinence challenge, some RNC conditions relative to NNC condition exhibited reduced withdrawal. Individuals who were biochemically confirmed as adherent to the lowest nicotine condition experienced only mild and transient symptom elevations. Thus, a reduced-nicotine standard for cigarettes produced a relatively mild and temporary increase in withdrawal among nontreatment-seeking smokers (ClinicalTrials.gov No. NCT01681875). (PsycINFO Database Record 10.1037/pha0000179