Nicotine Withdrawal Symptoms Research Articles

Can exercise alleviate sleep disturbances during acute nicotine withdrawal in cigarette smokers?

Sleep disturbances, including insomnia (difficulty falling or staying asleep), are common nicotine withdrawal symptoms particularly during the initial stage of nicotine abstinence, and increase the likelihood of relapse within the first 4 weeks of quitting. Although clinically recognized as a key symptom of nicotine withdrawal, sleep disturbances are not addressed in the clinical guidelines for nicotine dependence treatment. Unfortunately, Nicotine Replacement Therapy (NRT) and other pharmacologic interventions do not attenuate withdrawal-provoked sleep disturbances, with several even exacerbating sleep disruption. The present study tested the impact of 30-min of daily moderate exercise, morning versus evening, on key polysomnographic indicators of sleep disturbances during initial 3 days (72 hr) of nicotine withdrawal. Forty-nine daily smokers (53% male) completed 3 separate abstinence periods, during which they completed either morning exercise, evening exercise, or a nonexercising magazine reading control condition. Order of condition was counterbalanced across subjects with a 1-week wash out in between each 3-day abstinence period. Exercise engagement mitigated several changes in sleep architecture associated with acute nicotine deprivation and other time-related effects on sleep, specifically frequency of arousals (B = -2.8, SE = .95; t(1271) = -3.0, p = .003) and reductions in sleep maintenance (B = .58, SE = .21; t(1270) = 2.8, p = .005). Additionally, smokers who reported greater perceived withdrawal severity had the longest latency to fall asleep but experienced the greatest attenuation of this effect following PM exercise. Overall, results suggest a role for exercise as an adjunct smoking cessation treatment to specifically target sleep disturbances during early acute nicotine withdrawal. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Progesterone Aids in Alleviation of Nicotine Withdrawal Symptoms: A Systematic Review

Background: A systematic review of studies on progesterone’s usage in the cure of nicotine craving was undertaken. Progesterone is a steroid hormone that influences the reproductive system as well as -Aminobutyric acid type A (GABAA) receptors, glycine, kainite, and nicotinic receptors. It is thought that progesterone might help with nicotine withdrawal symptoms in addicted people. Method: Two authors completed the literature search independently using the Boolean search approach and searching key terms (i.e. progesterone AND treat*, drug addiction AND withdrawal, smok*, nicotine), screened the title, abstract and full-text for data extraction during June 2021. A search in the PubMed, NIH, Elsevier, Scopus, Web of Science, Google Scholar, and Science Direct databases was performed. The review included seven (7) articles out of seventy-eight (78) downloaded articles that met the inclusion criteria. Microsoft Excel and IBM SPSS were used for statistical analysis. Results: These studies included 147 males and 377 females, out of which 46 were pregnant. The average age ranged between 18 and 45 years. The participants included those who had smoked 10-25 cigarettes/day for a year. The carbon monoxide measuring over 10ppm signifies recent smoking was found in 10% (n=12) participants who were given 400mg progesterone, 11% (n=14) for the 200 mg progesterone, and 13% (n=16) for the placebo groups. The progesterone prescription of 400 mg/day was effective in decreasing cravings to smoke, while the 200 mg dose helped with improving cognitive performance. Females in the progesterone group exhibited significantly lower smoking craving scores than females in the placebo group. A significant difference has been observed in 7-day PPA at week 4 among women i.e. “PRO: 18 (35.3%) vs. PBO: 9 (17.3%), Odds Ratio: 2.61 (95% confidence interval) and p=0.041”, but not among men i.e. “PRO: 13 (23.2%) vs. PBO: 12 (21.1%), 1.13 (0.47, 2.76) and p=0.782”. There was some evidence that PRO delayed relapse in women (Days to Relapse; PRO: 20.5 ±29.6 vs. PBO: 14.3 ±26.8, p=0.03) but not in men (PRO: 13.4 ±25.9 vs. PBO: 13.3 ± 23.8, p=0.69). Nearly half of the females who smoke before pregnancy can quit smoking during pregnancy. However, 40-52% reverts within 2 weeks while 70-80% resumes smoking within a year of childbirth. Conclusion: In the majority of instances, 200mg was administered, and favorable outcomes were obtained. Although there were no major side effects observed, a few moderate side effects such as breast tenderness were reported in a few individuals. As a result, progesterone therapy helps to alleviate nicotine withdrawal symptoms, lowers smoking intensity, and treats smoking addiction in both men and women. Keywords: progesterone, prescription, treatment, drug addiction, withdrawal, smoking, nicotine

Advances in the Study of Neural Mechanisms Associated with Exercise to Ameliorate Nicotine Addiction

Objective: The objective is to elucidate the effectiveness of exercise as smoking cessation aid by sorting out the neurotransmitter basis of nicotine addiction and combining it with the neurotransmitter modulation effect of exercise, and finally to organize and analyze the mechanisms related to exercise to ameliorate nicotine addiction. Methods: We searched the Web of Science and PubMed databases for keywords, including “nicotine addiction”, “exercise”, “sports”, “physical activity”, “smoking cessation” and “tobacco withdrawal”, and compiled and analyzed the relevant literature to explain the neurobiological mechanisms of nicotine addiction and the effects of exercise on ameliorating nicotine addiction and related mechanisms. Results: 1) long-term nicotine intake, on the one hand, binds to acetylcholine receptors to produce rewarding effects, and on the other hand, causes rewarding effects by regulating the release of various neurotransmitters and signaling, making smokers feel pleasure and experiencing withdrawal symptoms after stopping smoking; 2) exercise can effectively ameliorate nicotine addiction; 3) exercise reduces the desire to smoke by activating the reward system to cause the body to release dopamine, partially replacing the rewarding effects and reducing withdrawal symptoms. Conclusion: Exercise is effective in ameliorating nicotine addiction through the modulation of neurotransmitters and improves the health status of people who quit smoking. Therefore, physical activity and physical exercise during smoking cessation are recommended to reduce nicotine withdrawal symptoms and smoking cravings.

Effectiveness of Nicotine Withdrawal Symptoms Management Program Using LINE Application to Increase Self-Efficacy for Industrial Workers

Background: Smoking is a risk factor for chronic diseases. A combination of tobacco use with occupational hazards among industrial workers could increase the risk of occupational disease and injury. Nicotine is known to be highly addictive. It is difficult not only to maintain the decrease in smoking but also to continue quitting tobacco use. Moreover, nicotine withdrawal can be challenging and lead to failure in the smoking cessation process. Self-efficacy theory has been used recently for the development of effective smoking cessation programs. Objective: To develop an online nicotine withdrawal symptoms management program based on self-efficacy theory and examine its effectiveness. Materials and Methods: A quasi-experimental design with a control group pretest-posttest design was used. The sample consisted of male employees working in a consumer product manufacturing industry in Bangkok. An intervention group (n=28) received an online nicotine withdrawal symptoms management program via LINE application based on self-efficacy theory for one month. In comparison, participants in the control group (n=29) received a conventional smoking cessation program. The effectiveness of the intervention on nicotine withdrawal symptoms, cigarette craving, self-efficacy perception of nicotine withdrawal management, cigarette rolls per day, nicotine dependence level, exhaled carbon monoxide level, and smoking cessation behavior the first and fourth week were examined using a repeated-measures analysis of variance. Results: At one-month follow-up, there were significant differences between the two groups on nicotine withdrawal symptoms score, cigarette craving level, self-efficacy perception of nicotine withdrawal management, cigarette rolls per day, nicotine addiction level, exhaled carbon monoxide level, and smoking cessation behaviors (p<0.001). In addition, there was a significant difference in the self-reported nicotine withdrawal symptoms score in terms of irritability, anger, anxiety, concentration deficit, depression, and insomnia (p<0.001) between groups, between times, and between times and groups (p<0.001). Conclusion: Nicotine withdrawal symptoms management program using LINE application is effective in encouraging smoking cessation. Keywords: Smoking cessation; Nicotine withdrawal symptoms; LINE application; Industrial workers

Preliminary Evaluation of Short-Term Abstinence Effects Among Never-Smoking Experienced Users of Modern Electronic Cigarettes.

ECIG use has increased among non-smokers, with the potential negative consequence of developing nicotine dependence. ECIG users report withdrawal symptoms upon abstinence, though the significance of these symptoms has been questioned. This preliminary study aimed to characterize the early timecourse of ECIG withdrawal under forced abstinence. Fifteen never-smoking ECIG users completed two conditions whereby participants either abstained from ECIG use (abstinence) or used their own ECIG (ad lib) for 3 h. Puff topography in this latter condition was measured via video observation. Outcome measures included heart rate, subjective ratings of withdrawal, cognitive performance, and choice behavior. Heart rate was lower during abstinence compared to ad lib use (F = 12.60, p < .01, ƞp2 = 0.47). Higher levels of craving (F = 4.98, p < .05, ƞp2 = 0.26) and lower levels of nicotine effects (e.g., dizzy, F = 4.62, p < .05, ƞp2 = 0.36) were reported during abstinence compared to ad lib use. Interaction effects were observed for both factors of the Questionnaire of Smoking Urges: Brief (Fs > 3.56, ps < .05, ƞp2s = 0.21-0.27), with factor scores increasing from baseline to 90 min in the abstinent condition only. Inhibitory control was impaired at 120 min in the abstinent condition only (F = 7.51, p < .05, ƞp2 = 0.50). Never-smoking ECIG users experienced aversive withdrawal symptoms within 2-3 h of abstinence. Future work should include other control conditions, such as placebo ECIGs or nicotine replacement therapy, and biomarkers of nicotine exposure, as well as examine withdrawal as a function of device type. Never-smoking ECIG users experience some aversive nicotine withdrawal symptoms within two to three hours of abstinence. Relative to ad lib ECIG use, abstinence decreased heart rate and inhibitory control, as well as increased subjective ratings of withdrawal such as craving and intention to vape. Those same symptoms might be suppressed by self-administration of ECIGs. Experiencing withdrawal upon abstinence may indicate that ECIGs can cause dependence without a history of other tobacco use.

Integrating a simple and brief home-based exercise programme within a UK stop smoking service: a mixed method feasibility study

BackgroundSmoking remains a leading cause of morbidity and mortality. Exercise improves physical health and reduces cigarette cravings and nicotine withdrawal symptoms, but has required attendance at multiple sessions using specialised equipment that limits delivery in a service. The purpose of this study was to test the feasibility of delivering a simple and brief home-based exercise intervention with existing smoking cessation support in a stop-smoking service. MethodsWe used a mixed-methods approach in a UK stop-smoking service operating from general practitioner surgeries and libraries near the most deprived areas in Surrey. Smokers recruited through the service gave written consent and received a 12-week exercise programme that included 5 min of home-based jumping activities and an activity diary with educational instructions 1 week before their quit date. Feasibility was assessed by recruitment, retention, adherence to the exercise programme, and follow-up and completion of assessments. Semi-structured interviews with trial participants (n=16), people who declined to take part (n=21), and smoking cessation advisors (n=10) assessed views and attitudes to participation and delivery of the intervention. Interviews were audio-recorded, transcribed verbatim, and analysed using thematic analysis (NVivo, version 12.0). Findings30 eligible trial participants consented, with 14 (47%) lost to follow-up, 16 participants (eight females, eight males; mean age 48 years [SD 11]) completed a mean of 47 (SD 18) of 74 prescribed exercise sessions over the 12-week period, resulting in 63% adherence. The exercise programme was received positively by most who engaged with it; fitting into their daily routine was an important outcome for completion. Of the participants who declined to take part (15 females, six males; mean age 48 years [SD 12]), many were positively disposed to the idea of participation, especially if the programme could be offered later in their treatment. All smoking cessation advisors (six females, four males; mean age 48 years [SD 20]) were supportive of the exercise programme, but several favoured the delivery by someone independent of the service. InterpretationA simple and brief exercise intervention may be feasible for smokers receiving smoking cessation treatment in a UK stop-smoking service. However, substantial attrition and non-compliance, along with some delivery components, need to be addressed before to a definitive trial. FundingMedical Research Council Public Health Intervention Development Scheme (MR/P017142/1).

A Randomized Trial of Nicotine versus No-nicotine E-cigarettes Among African American Smokers: Changes in Smoking and Tobacco Biomarkers.

The objective of this clinical trial was to compare the effects of e-cigarettes with and without nicotine on patterns of combustible cigarette use and biomarkers of exposure to tobacco toxicants among African American smokers. African American smokers (n = 234) were enrolled in a 12-week, single blind, randomized controlled trial and assigned to ad lib use of nicotine e-cigarettes with or without menthol (2.4% nicotine [equivalent to combustible cigarettes], n = 118), or no-nicotine e-cigarettes (n = 116) for 6 weeks. Surveys were administered at baseline, 2, 6, and 12 weeks, and urinary biomarkers 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and total nicotine equivalents (TNE) were assessed at baseline and 6 weeks. Participants smoked an average of 11.4 cigarettes per day (CPD) and 88% used menthol cigarettes at baseline. At Week 6, the nicotine group reported using e-cigarettes 9.1 times per day compared to 11.4 times in the no-nicotine group (p = 0.42). Combustible cigarette smoking decreased 3.0 CPD in the nicotine group compared to 2.7 CPD in the no-nicotine group (p = 0.74). Neither TNE nor NNAL changed significantly between baseline and Week 6. There were no differences in nicotine withdrawal symptoms between treatment groups. Smoking reduction persisted in both groups at Week 12. Contrary to our hypotheses, nicotine e-cigarettes did not significantly reduce the use of combustible cigarettes compared to no-nicotine e-cigarettes in this cohort of African American smokers. Findings suggest e-cigarettes are modestly associated with the decreased use of combustible cigarettes among non-treatment seeking smokers, regardless of nicotine content, but without a reduction in tobacco toxicants. Although e-cigarettes have the potential to reduce harm if substituted for combusted cigarettes (or if they promoted cessation) because of lower levels of tobacco toxicants, this study suggests ad lib use of e-cigarettes among African American smokers, with or without nicotine, results in modest smoking reduction but does not change toxicant exposure in a cohort where smoking cessation or reduction is not the goal. These data suggest that testing future harm reduction interventions using e-cigarettes should include more specific behavioral change coaching, including substituting for or completely stopping combusted cigarettes. ClinicalTrials.gov - NCT03084315.

Lacidipine Attenuates Symptoms of Nicotine Withdrawal in Mice.

Nicotine-withdrawal after daily exposure manifests somatic and affective symptom including a range of cognitive deficits. Earlier studies suggested participation of L-type calcium channels (LTCCs) in development of nicotine dependence and expression of withdrawal signs. An upsurge in Ca2+-induced oxidative stress in brain underlies the biochemical events and behavioral signs of nicotine-withdrawal. The present study is aimed to explore the effects of lacidipine (LTCC antagonist) against nicotine-withdrawal. Swiss albino mice were administered ( -)-nicotine hydrogen tartrate (3.35mg/kg, t.i.d.) from days 1 to 7 and alongside lacidipine (0.3, 1, and 3mg/kg, i.p.) given from days 1 to 14. Somatic withdrawal signs were noted 48h after last dose of nicotine. Bay-K8644 (LTCC agonist) was administered in mice subjected to nicotine-withdrawal and lacidipine (3mg/kg) treatments. Behavioral tests of memory, anxiety, and depression were conducted on days 13 and 14 to assess the effects of lacidipine on affective symptoms of nicotine-withdrawal. Biomarkers of oxido-nitrosative were quantified in the whole brain. Nicotine-withdrawal significantly enhanced somatic signs and symptoms of anxiety, depression, and memory impairment in mice. Lacidipine (1 and 3mg/kg) attenuated nicotine-withdrawal induced somatic symptoms and also ameliorated behavioral abnormalities. Nicotine-withdrawal triggered an upsurge in brain lipid peroxidation, total nitrite content, and decline in antioxidants, and these effects were attenuated by lacidipine. Bay-K8644 significantly abolished improvement in somatic and affective symptoms, and antioxidant effects by lacidipine in mice subjected to nicotine-withdrawal. Lacidipine mitigated nicotine-withdrawal triggered somatic and affective symptoms owing to decrease in brain oxido-nitrosative stress.

Effect 1 of NMDA Receptor Agonist and Antagonist on Nicotine withdrawal induced Hyperexcitability in Mice

Kynurenic acid is a recognized broad-spectrum antagonist of excitatory amino acid receptors with a particularly high affinity for the glycine co-agonist site of the N-methyl-D-aspartate (NMDA) receptor complex. D- Cycloserine is a NMDA receptor partial agonist which facilitate in an initiation of nicotine withdrawal symptoms and dependence. Thus, the influence of kynurenic acid treatment on the development and expression of nicotine dependence was tested by using the nicotine withdrawal-induced hyperexcitability paradigm. Mice were provided with a nutritionally balanced control liquid diet as the sole nutrient source on day 0; from day 1–4 (nicotine 25µg), from day 5–7 (nicotine, 50ug) and from day 8–10 (nicotine, 100ug) was incorporated into the liquid diet. On day 11, the nicotine liquid diet was replaced with nutritionally balanced control liquid diet, and nicotine withdrawal-induced hyperexcitability signs were recorded. The results revealed that acute administration of kunurenic acid (50 and 100mg/kg, i.p.) dose-dependently attenuated nicotine withdrawal-induced hyperexcitability signs, and these results were comparable to D- Cycloserine (50 and 100mg/kg, i.p.) Further, chronic administration of kunurenic acid (50 and 100mg/kg, i.p.) to the nicotine diet fed mice markedly attenuated the nicotine withdrawal-induced hyperexcitability signs. In conclusion, the results and evidence suggest that kinurenic acid exhibited an inhibitory influence against nicotine withdrawal-induced hyperexcitability signs, which could be mediated through its neuromodulatory action.

Anxiety, Depression, Psychological Symptoms, Negative Effects, and Other Symptoms of Nicotine Withdrawal

This case occurred in a 33-year-old man who has been smoking for 19 years. He had a pattern of consuming 14 cigarettes per day with 30 mg of nicotine intake and high tar levels. The level of tolerance for consumption of nicotine and tar per day is 10 to 15 mg. High cigarette consumption correlates with high nicotine consumption as well. Excessive nicotine consumption over a long period can lead to lung cancer, stroke, heart disease, chronic obstructive pulmonary disease, and psychological disorders.

The effect of nicotine dependence and withdrawal symptoms on use of nicotine replacement therapy: Secondary analysis of a randomized controlled trial in primary care

IntroductionNicotine replacement therapy (NRT) is effective for smoking cessation, but the optimal method of using NRT to maximize benefit is unclear. We examined whether nicotine dependence was associated with consumption of NRT, whether this was mediated by withdrawal symptoms, and the impact of these factors on cessation, in a population advised to use as much NRT as needed. MethodsSecondary analysis of data from an open label, parallel group randomized controlled trial. Participants (n = 539) attended a smoking cessation clinic in primary care and remained engaged with treatment for at least one week following a quit attempt. Baseline dependence was measured by the Fagerström Test for Cigarette Dependence (FTCD), with tobacco exposure assessed via an exhaled carbon monoxide test. At one week after quit day, mean daily consumption of NRT was measured for all participants; withdrawal (Mood and Physical Symptoms Scale (MPSS)) was also assessed in the subsample who reported being completely abstinent to that point (n = 279). Abstinence was biochemically assessed at four weeks for all participants as the principal smoking cessation outcome. ResultsEach point higher on the FTCD was associated with 0.83 mg/day more NRT consumption, controlling for tobacco exposure. This relationship was diminished when withdrawal was controlled for, and withdrawal was associated with NRT consumption, with each point higher on the MPSS associated with a 0.12 mg/day increase. Increased consumption of NRT directly predicted subsequent smoking cessation. ConclusionsHigher dependence appears to lead to greater withdrawal, which appears to drive greater use of NRT. This effect may partly offset lower abstinence rates in people with higher dependence. Advice to use sufficient NRT to suppress withdrawal may increase abstinence rates.

Smoking: Pathogenetic Mechanisms, Possibilities of Medical Correction (Literature Review)

The smoking epidemic is one of the greatest threats to human health, as it is the leading cause of death worldwide, as well as many preventable diseases. Diseases associated with smoking include cardiovascular disease, atherosclerosis, type 2 diabetes, chronic pancreatitis, chronic obstructive pulmonary disease, cancer, osteoporosis and others. The aim is to analyze information on the pathogenetic mechanisms of tobacco exposure and methods of its drug correction. Among the 4,000 chemicals identified in tobacco smoke, nicotine is the main active ingredient in tobacco products. It is highly toxic and potentially lethal. Nicotine affects many systems, including the neurological, neuromuscular, cardiovascular, respiratory, immunological and gastrointestinal systems. Therefore, nicotine-containing drugs reduce the symptoms of nicotine withdrawal in regular smokers who abstain from smoking. The presence of different types of nicotinic acetylcholine receptors, their regulation and desensitization affect these complex physiological effects. Nicotine replacement drugs contain pure nicotine, in order to reduce the patient’s propensity to use tobacco, physiological and psychomotor withdrawal symptoms. They increase the level of nicotine in the blood, thus facilitating the transition from cigarette smoking to complete abstinence. Smokers can quit without using nicotine-containing drugs, but most those who try do not succeed on the first try. Nicotine replacement drugs only affect physical dependence. Nicotine is the main factor responsible for dependence on cigarette smoking, and its rate of absorption and entry into the brain are considered key factors responsible for the high potential for abuse of this drug. The advantage of nicotine-containing drugs is the patient’s independence from the method of administration, determination of abstinence, duration of treatment, level of supportive counseling, place of treatment (hospital, clinic or support group), as well as fixed, variable or reduced doses. There are a number of nicotine-containing drugs in various forms that effectively promote smoking cessation in adults.

Dynamic activity of interpeduncular nucleus GABAergic neurons controls expression of nicotine withdrawal in male mice.

A critical brain area implicated in nicotine dependence is the interpeduncular nucleus (IPN) located in the ventral midbrain and consisting primarily of GABAergic neurons. Previous studies indicate that IPN GABAergic neurons contribute to expression of somatic symptoms of nicotine withdrawal; however, whether IPN neurons are dynamically regulated during withdrawal in vivo and how this may contribute to both somatic and affective withdrawal behavior is unknown. To bridge this gap in knowledge, we expressed GCaMP in IPN GABAergic neurons and used in vivo fiber photometry to record changes in fluorescence, as a proxy for neuronal activity, in male mice during nicotine withdrawal. Mecamylamine-precipitated withdrawal significantly increased activity of IPN GABAergic neurons in nicotine-dependent, but not nicotine-naive mice. Analysis of GCaMP signals time-locked with somatic symptoms including grooming and scratching revealed reduced IPN GABAergic activity during these behaviors, specifically in mice undergoing withdrawal. In the elevated plus maze, used to measure anxiety-like behavior, an affective withdrawal symptom, IPN GABAergic neuron activity was increased during open-arm versus closed-arm exploration in nicotine-withdrawn, but not non-withdrawn mice. Optogenetic silencing IPN GABAergic neurons during withdrawal significantly reduced withdrawal-induced increases in somatic behavior and increased open-arm exploration. Together, our data indicate that IPN GABAergic neurons are dynamically regulated during nicotine withdrawal, leading to increased anxiety-like symptoms and somatic behavior, which inherently decrease IPN GABAergic neuron activity as a withdrawal-coping mechanism. These results provide a neuronal basis underlying the role of the IPN in the expression of somatic and affective behaviors of nicotine withdrawal.

Activation of trace amine-associated receptor 1 attenuates nicotine withdrawal-related effects.

Nicotine addiction is a leading avoidable brain disorder globally. Although nicotine induces a modest reinforcing effect, which is important for the initial drug use, the transition from nicotine use to nicotine addiction involves the mechanisms responsible for the negative consequences of drug abstinence. Recent study suggested that trace amine-associated receptor 1 (TAAR1) is a promising pharmacological target for the modulation of positive reinforcing effects of nicotine. However, whether TAAR1 plays a part in the negative reinforcement of nicotine withdrawal remains to be determined. Here, using a long-access (LA) self-administration model, we investigated whether LA rats show increased nicotine intake and withdrawal symptoms in comparison with saline and ShA rats and then tested the effect of TAAR1 partial agonist RO5263397 on nicotine withdrawal effects. We found that rats from long-access group showed significant abstinence-induced anxiety-like behaviour, mechanic hypersensitivity, increased number of precipitated withdrawal signs and higher motivation for the drug, while rats from short-access did not differ from saline group. TAAR1 partial agonist RO5263397 significantly reduced the physical and motivational withdrawal effects of nicotine in LA rats, as reflected by increased time spent on the open arm in the elevated plus maze (EPM) test, normalized paw withdrawal threshold, decreased withdrawal signs and motivation to self-administer nicotine. This study indicates that activation of TAAR1 attenuates the negative-reinforcing effects of nicotine withdrawal and further suggests TAAR1 as a promising target to treat nicotine addiction.

Vitamin D3 reduces hippocampal NR2A and anxiety in nicotine withdrawal mice.

Nicotine withdrawal symptoms, mainly anxiety, cause high level of relapse rate after quitting smoking. Vitamin D supplementation has shown its potential for the prevention and treatment of anxiety disorders; however, neurobiological studies about the effect of vitamin D on nicotine withdrawal-induced anxiety are limited. To investigate the effect and molecular mechanism of vitamin D3 supplement by dietary on anxiety-like behavior during nicotine withdrawal, male C57/BL6 mice were divided into four groups: vehicle, nicotine only, vitamin D3 only, and nicotine plus vitamin D3. Mice were administrated with nicotine in drinking water (200 µg/mL), and vitamin D3 in feed for 6 weeks. During nicotine withdrawal, vitamin D3-treated mice showed significantly less anxiety-like behavior by an open-field test and marble buried test that performed an increase in the duration of the central zone and a decrease buried marble, respectively. Moreover, vitamin D3 supplementation attenuated the hippocampal NR2A expression on both protein and mRNA levels in nicotine and vitamin D3-treated mice. Our data showed that dietary supplementation with vitamin D3 ameliorated nicotine withdrawal-induced anxiety, which may be related to downregulation of NR2A expression in hippocampus. Vitamin D3 may provide a new dietary intervention with the easy access for smoking cessation.

Pharmacokinetic Characterization of a Prototype Mini Nicotine Lozenge.

Cigarette smoking remains a substantial public health problem. Nicotine replacement therapy (NRT) is an effective treatment that increases the success of a quit attempt. There are different NRT formats with no difference in efficacy, but their pharmaceutical form or route of administration may translate into individual preferences. A novel prototype mini lozenge was developed to offer smokers a new NRT option to aid in their quit attempt. Two studies were conducted to characterize the pharmacokinetic parameters and to evaluate its bioequivalence to a commercially available nicotine mini lozenge. Two randomized, open-label, crossover studies were conducted to evaluate either the 2 or 4mg dose level. Heavy smokers in otherwise good health were randomly assigned to one of two treatment sequences: the prototype mini lozenge followed by a commercially available mini lozenge, or the converse. After a 5 to 7day washout period, subjects crossed over to receive the other study treatment. Blood sampling occurred pre- and post-dose nicotine and was assessed using a validated solid-phase extraction with ultra-high-performance liquid chromatography and tandem mass spectrometry. The primary endpoint was bioequivalence as determined by maximal plasma nicotine concentration (Cmax) and the extent of nicotine absorption (AUC0-t and AUC0-∞). The secondary endpoints included the time to Cmax (Tmax), half-life, the elimination constant (Kel), and safety. The prototype mini lozenge was bioequivalent to the commercially available mini lozenge, with no significant difference in Cmax, AUC0-t, or AUC0-∞ or any of the secondary outcomes. The most common treatment-emergent adverse event was throat irritation, of which all cases were mild in severity. There were no serious adverse events. The prototype mini lozenge is bioequivalent to a commercially available mini lozenge and may provide smokers with a new oral NRT option to aid in smoking cessation and of tobacco dependence through the relief of nicotine withdrawal symptoms, including cravings.

Evaluating appropriate use of nictoine replacement therapy on acute adult psychiatric units and adverse events related to smoking bans on wards

AimsTo assess if patients are offered appropriate and adequate NRT (nicotine replacment therapy) upon admission to an acute adult inpatient ward.To evaluate the number of adverse events occurring which are related to mandatory temporary abstinence from cigarette smoking on inpatient wards.BackgroundNot all patients are able or willing to quit smoking when admitted to secondary care. In line with NICE Guidance, psychiatric inpatients should not be permitted to smoke inside the hospital building or outside on hospital grounds. NRT is the most widely used smoking cessation aid. It aims to temporarily replace the nicotine from cigarettes to reduce motivation to smoke and nicotine withdrawal symptoms.. NRT should be offered to patients who need support with nicotine withdrawal during an inpatient stay. Trust guidelines state nursing staff are able to administer NRT to patients on admission without prescription, reducing cravings and withdrawal symptoms such as agitation and anxiety which can lead to adverse events such as aggressive behaviour. Cravings may result in the patients self-discharging or absconding from the ward to smoke.MethodA retrospective review of electronic records was conducted of all inpatients admitted to two acute adult units over a three month period (65 patients). Patients were identified as smokers or non-smokers. Search words used included: ‘smoking’, ‘NRT’, ‘nicotine’, ‘cig’ to search for relevant entries. Data collected included whether NRT was offered and given by nursing staff on admission and adverse events related to smoking.ResultData from 65 patient admissions were reviewed (31 males, 34 females, mean age 37 years). 37 (57%) patients were identified as smokers. NRT was offered and accepted by 17% of patients on admission and not recorded in 77% of admissions. NRT was declined when offered by 3% of patients.Adverse events related to smoking occurred in 38% of ‘smoking’ patients. 40% of these adverse events occurred in first 72 hours of admission. Adverse events include verbal conflicts, physical aggression towards nursing staff and smoking in patient areas.ConclusionThe majority of patients were not offered NRT on admission or this was not accurately documented in clinical notes. When offered NRT, a large proportion of patients accepted it demonstrating its acceptability amongst this patient group. There is a high rate of adverse events related to smoking on wards. More accurate documentation is required to ensure NRT is being sufficiently offered to patients to reduce possible withdrawal symptoms and adverse events.

Association of NRG3 and ERBB4 gene polymorphism with nicotine dependence in Turkish population.

Nicotine dependence (ND) is characterized by regular smoking, anxiety, irritation, difficulty concentrating, impatience, restlessness, tremor, dizziness, hunger, nicotine demand, and the individual's reluctance to quit despite knowing the health risks of smoking. Recently, it has been reported that the Neuregulin 3 (NRG3)/Erb-B2 receptor tyrosine kinase 4 (ERBB4) signaling pathway plays a role in ND. NRG3, which is activated after nicotine intake, binds to ERBB4 and causes GABA release. GABA reduces anxiety and tension, which are one of the nicotine withdrawal symptoms. Therefore we aimed to investigate the relationship between NRG3 and ERBB4 gene polymorphisms and ND. The study population was comprised of patients with ND (n = 200) and healthy non-smoker control subjects (n = 200) who were matched for age, sex, and compared for comorbidity factors such as alcohol, smoking, duration, and education (age range 18-60). Genotypes were detected by Real-Time PCR using TaqMan technology. The Fagerström Nicotine Dependence Test (FTND) score was 5 and above for the patient group and 0 for the control group. DNA was obtained from whole peripheral blood and six polymorphisms of Neuregulin 3 (NRG3) (rs1836724, rs7562566, and rs10048757) and Erb-B2 Receptor Tyrosine Kinase 4 (ERBB4) (rs1764072, rs6584400, and rs10883934) genes were analyzed by real-time PCR method. Our findings show that the six selected SNPs are not significantly associated with ND in the Turkish population and no correlation with dependence levels (p > 0.05). Although our findings do not show a relationship between ND and these polymorphisms, it is the first study to investigate these single nucleotide polymorphisms (SNPs) for the first time in ND and to find some genotypes in the Turkish population when compared to other populations. Also, our findings are important in terms of their contribution to the literature and forensic genetics.

Serotonin neurons in the median raphe nucleus bidirectionally regulate somatic signs of nicotine withdrawal in mice

In chronic smokers, nicotine withdrawal symptoms during tobacco cessation can lead to smoking relapse. In rodent models, chronic exposure to nicotine elicited physical dependence, whereas acute antagonism of nicotinic acetylcholine receptors (nAChRs) immediately precipitated withdrawal symptoms. Although the central serotonergic system plays an important role in nicotine withdrawal, the exact serotonergic raphe nuclei regulating these symptoms remain unknown. We used transgenic mice expressing archaerhodopsinTP009 or channelrhodopsin-2[C128S] exclusively in the central serotonergic neurons to selectively manipulate serotonergic neurons in each raphe nucleus. Nicotine withdrawal symptoms were precipitated by an acute injection of mecamylamine, a nonspecific nAChR antagonist, following chronic nicotine consumption. Somatic signs were used as measures of nicotine withdrawal symptoms. Acute mecamylamine administration significantly increased ptosis occurrence in nicotine-drinking mice compared with that in control-drinking mice. Optogenetic inhibition of the serotonergic neurons in the median raphe nucleus (MRN), but not of those in the dorsal raphe nucleus (DRN), mimicked the symptoms observed during mecamylamine-precipitated nicotine withdrawal even in nicotine-naïve mice following the administration of acute mecamylamine injection. Optogenetic activation of the serotonergic neurons in the MRN nearly abolished the occurrence of ptosis in nicotine-drinking mice. The serotonergic neurons in the MRN, but not those in the DRN, are necessary for the occurrence of somatic signs, a nicotine withdrawal symptom, and the activation of these neurons may act as a potential therapeutic strategy for preventing the somatic manifestations of nicotine withdrawal.

Effects of Chronic Nicotine Exposure and 24h Withdrawal on Synaptosomal Protein Expression in the Mouse Ventral Hippocampus

Despite cigarette smoking being the leading cause of preventable death in the United States 20% of Americans continue to smoke. We now know that 80% of smokers desire to quit; however, less than 5% of them are successful. The low success rate of smoking cessation is partially due to current pharmacotherapies only addressing a subset of nicotine withdrawal symptoms, which is the primary driver of smoking relapse. A prominent, yet unaddressed, symptom of nicotine withdrawal is affective dysfunction. Affective symptoms, such as increased anxiety and reduced emotional regulation, are underpinned by discrete disruption of select brain circuits. For example, the ventral hippocampus (VHIPP) has a well-described role sub-serving the interface between contextual learning and affective responding, suggesting it as a potential circuitry target for examination of molecular alterations during nicotine withdrawal. Therefore, we explored this by treating 18-week-old mice for two weeks with either saline, nicotine (18 mg/kg/day), or 24h withdrawal from nicotine (18 mg/kg/day) via osmotic minipumps (Alzet 2002 model). Following treatment, the subjects were sacrificed and the VHIPP was collected and synaptosomes were prepared. These samples were analyzed via liquid chromatography-mass spectrometry to quantify changes in synaptosomal protein expression. These results were then analyzed using Enrichr pathway and transcriptional factor databases. Our results indicate changes in the axon guidance, vesicle-mediated transport, and transmission across chemical synapses pathways in both nicotine versus saline and withdraw versus saline synaptosomal protein comparisons. However, upon qPCR analysis mRNA expression of key genes associated with the pathways of interest remained unchanged for each treatment group. Further experiments will utilize western blotting to validate changes in total and phosphorylated proteins of interest in the aforementioned pathways.