Varenicline serves as the training stimulus in the drug-discriminated goal-tracking task with rats: initial evaluation of potential neuropharmacological processes.

Varenicline (Chantix) is an FDA-approved smoking cessation aid that is pharmacologically similar to nicotine, the primary addictive component found within tobacco. In support of this similarity, previous drug discrimination research in rats has reported that the internal or interoceptive stimulus effects of nicotine and varenicline share stimulus elements. Those shared elements appear to be mediated, in part, by overlapping action at alpha4beta2-containing nicotinic acetylcholine receptors (nAChRs). The research supporting this conclusion, however, has only used nicotine, and not varenicline, as the training drug. Accordingly, we used the discriminated goal tracking (DGT) task in which 1 mg/kg varenicline signaled intermittent access to sucrose. On separate intermixed saline days, sucrose was not available. Rats acquired the discrimination as measured by a differential increase in dipper entries (goal tracking) evoked by varenicline. These rats then received a series of tests with several doses of varenicline, nicotine, nornicotine (a metabolite of nicotine and tobacco alkaloid), sazetidine-A (a partial alpha4beta2 agonist), PHA-543613 (an alpha7 agonist), and bupropion (a norepinephrine and dopamine reuptake inhibitor). Control of goal tracking by varenicline was dose-dependent. Nicotine and nornicotine evoked responding comparable to the varenicline training dose indicating full substitution. Sazetidine-A partially substituted for the varenicline stimulus, whereas bupropion and PHA-543613 evoked little to no varenicline-like responding. These findings indicate that varenicline can serve as the training stimulus in the DGT task. Further, stimulus control of varenicline in the DGT task is driven by its partial agonist activity at alpha4beta2-containing nAChRs. The use of this approach could lead to a better understanding of the pharmacological action of varenicline and help guide treatment geared towards tobacco cessation through a more targeted development of novel synthetically designed, subunit-specific pharmacological interventions.

Tobacco Use Disorder.

Tobacco use disorder is highly prevalent; more than a billion individuals use tobacco worldwide. Popular views on the addictive potential of tobacco often underestimate the complex neural adaptations that underpin continued use. Although sometimes trivialized as a minor substance, effects of nicotine on behavior lead to profound morbidity over a lifetime of exposure. Innovations in processing have led to potent forms of tobacco and delivery devices. Proactive treatment strategies focus on pharmacotherapeutic interventions. Innovations on the horizon hold promise to help clinicians address this problem in a phenotypically tailored manner. Efforts are needed to prevent tobacco use for future generations.

Cytisine and cytisine derivatives. More than smoking cessation aids.

Cytisine, a natural bioactive compound that is mainly isolated from plants of the Leguminosae family (especially the seeds of Laburnum anagyroides), has been marketed in central and eastern Europe as an aid in the clinical management of smoking cessation for more than 50 years. Its main targets are neuronal nicotinic acetylcholine receptors (nAChRs), and pre-clinical studies have shown that its interactions with various nAChR subtypes located in different areas of the central and peripheral nervous systems are neuroprotective, have a wide range of biological effects on nicotine and alcohol addiction, regulate mood, food intake and motor activity, and influence the autonomic and cardiovascular systems. Its relatively rigid conformation makes it an attractive template for research of new derivatives. Recent studies of structurally modified cytisine have led to the development of new compounds and for some of them the biological activities are mediated by still unidentified targets other than nAChRs, whose mechanisms of action are still being investigated. The aim of this review is to describe and discuss: 1) the most recent pre-clinical results obtained with cytisine in the fields of neurological and non-neurological diseases; 2) the effects and possible mechanisms of action of the most recent cytisine derivatives; and 3) the main areas warranting further research.

Varenicline rescues nicotine-induced decrease in motivation for sucrose reinforcement.

Varenicline is one of the top medications used for smoking cessation and is often prescribed before termination of nicotine use. The effect of this combined nicotine and varenicline use on the reward system and motivation for primary reinforcement is underexplored. The goal of this study was to assess the effects of nicotine and varenicline on motivation for a food reinforcer. In Experiment 1, we first assessed the responding for sucrose after pretreatment with nicotine (0, 0.1, or 0.4 mg/kg) and varenicline (0.0, 0.1, 1.0 mg/kg) using a behavioral economics approach. The responding for sucrose was then assessed using a progressive ratio schedule of reinforcement after pretreatment with all possible combinations of nicotine and varenicline doses. In Experiment 2, rats were assessed for the consumption of sucrose in home cages after pretreatment with nicotine and varenicline. We found that (a) nicotine decreased economic demand for sucrose, (b) varenicline rescued nicotine-induced reduction in economic demand for sucrose, and (c) history of varenicline treatment predicted responding for sucrose on a progressive ratio schedule of reinforcement where rats with a history of varenicline treatment responded significantly lower for sucrose across nicotine doses than rats that had not been exposed to varenicline. The results of Experiment 2 largely confirmed that nicotine decreases motivation for sucrose using a passive consumption protocol and that varenicline rescues this effect. Overall, these findings suggest that varenicline interacts with the effects of nicotine by restoring nicotine-induced reduction in motivation for appetitive rewards.

The importance of acquisition learning on nicotine and varenicline drug substitution in a drug-discriminated goal-tracking task.

Nicotine and varenicline (Chantix®; the leading non-nicotine cessation pharmacotherapy) can come to control appetitive behaviors such as goal-tracking. We tested rats (N = 48) in a drug-discriminated goal-tracking (DGT) task where each rat received daily subcutaneous injections of either nicotine (0.4 mg/kg) or saline (0.9% [w/v]) interspersed across the acquisition phase (Phase 1). On saline days, sucrose was intermittently available. On nicotine days, sucrose was withheld. All rats acquired the discrimination with increased goal-tracking rates on saline days relative to nicotine days. Following acquisition, rats were separated into four groups to assess drug-substitution and discrimination reversal in Phase 2. The first group maintained the stimulus-reinforcer relation from acquisition (NIC-). The reversal group was now given access to sucrose on nicotine days (NIC+). The substitution group replaced nicotine with varenicline (1 mg/kg) while maintaining the acquisition stimulus-reinforcer relation (VAR-). The substitution and reversal group had nicotine replaced by varenicline and the stimulus-reinforcer relation reversed (VAR+). Rats in all groups learned or maintained their Phase 1 discriminations. For Phase 2, the reversal groups (+ conditions) acquired their discriminations within 10 sessions. The VAR- group displayed a pattern of disrupted discrimination at the outset of Phase 2 but was reestablished after continued training. In substitution testing, VAR groups received nicotine and NIC groups received varenicline. The NIC- and VAR- groups displayed full substitution of the test stimulus whereas the NIC+ and VAR+ groups displayed partial substitution of the test stimulus. Rats underwent nicotine extinction in Phase 3. Initial responding for each group mimicked Phase 2 training (i.e., higher responding by the reversal groups). All rats maintained similarly low levels of responding after six sessions. In conclusion, initial learning history with nicotine (i.e., + or -) influenced drug-stimulus substitution and the rate at which new learning (e.g., reversal) occurs with the varenicline and nicotine interoceptive stimuli.

Nicotine promotes brain metastasis by polarizing microglia and suppressing innate immune function.

Up to 40% of lung cancer patients develop brain metastasis, and the median survival of these patients remains less than 6 months. Smoking is associated with lung cancer. However, how smoking impacts the development of brain metastasis remains elusive. We examined 281 lung cancer patients with distant metastasis and found that smokers exhibited a significantly high incidence of brain metastasis. We found that nicotine enhanced brain metastasis, while a depletion of microglia suppressed this effect in vivo. Nicotine skewed the polarity of microglia to the M2 phenotype, thereby increasing the secretion of IGF-1 and CCL20, which promoted tumor progression and stemness. Importantly, nicotine enhanced the expression of SIRPα in microglia and restricted their phagocytic ability. We also identified a compound, parthenolide, that suppressed brain metastasis by blocking M2 polarization. Our results indicate that nicotine promotes brain metastasis by skewing the polarity of M2 microglia, which enhances metastatic tumor growth. Our results also highlight a potential risk of using nicotine for tobacco cessation.

Advances in the In vitro and In vivo pharmacology of Alpha4beta2 nicotinic receptor positive allosteric modulators.

Receptors containing α4 and ß2 subunits are a major neuronal nicotinic acetylcholine receptor (nAChR) subtype in the brain. This receptor plays a critical role in nicotine addiction, with potential smoking cessation therapeutics producing modulation of α4ß2 nAChR. In addition, compounds that act as agonists at α4ß2 nAChR may be useful for the treatment of pathological pain. Further, as the α4ß2 nAChR has been implicated in cognition, therapeutics that act as α4ß2 nAChR agonists are also being examined as treatments for cognitive disorders and neurological diseases that impact cognitive function, such as Alzheimer's disease and schizophrenia. This review will cover the molecular in vitro evidence that allosteric modulators of the α4ß2 neuronal nAChR provide several advantages over traditional α4ß2 nAChR orthosteric ligands. Specifically, we explore the concept that nAChR allosteric modulators allow for greater pharmacological selectivity, while minimizing potential deleterious off-target effects. Further, here we discuss the development and preclinical in vivo behavioral assessment of allosteric modulators at the α4ß2 neuronal nAChR as therapeutics for smoking cessation, pathological pain, as well as cognitive disorders and neurological diseases that impact cognitive function. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.

Preclinical and clinical research on the discriminative stimulus effects of nicotine.

Across species, nicotine can produce robust discriminative stimulus (DS) effects, as with other drugs of abuse, a feature that has been harnessed to advance our understanding on the neuropharmacological mechanisms of nicotine's actions. With the crucial role played by nicotine in supporting tobacco dependence, nicotine DS effects have presented an ideal platform to develop novel generation of smoking cessation compounds. Findings from preclinical strands of research have invigorated the field of human discrimination research to objectively assess nicotine's interoceptive stimulus effects. As such, translation studies provide proof of concept for nicotine DS research as a method to assess the subjective effects of nicotine per se, separate from non-nicotine stimuli involved in smoking. Recent clinical studies with low doses have demonstrated that perceiving nicotine's DS effects is necessary, yet not sufficient, for that dose to be reinforcing. These measures have been instrumental in developing novel strategies with regards to establishing threshold doses of nicotine contained in tobacco products, to then determine subthreshold doses that cannot be discriminated and, therefore, fail to maintain reinforcement. Findings from preclinical and clinical nicotine DS research could substantially inform public health policies aimed at regulating nicotine content of consumer products so that they minimize risks of dependency. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.

Assessment of individual differences in response to acute bupropion or varenicline treatment using a long-access nicotine self-administration model and behavioral economics in female rats.

Bupropion and varenicline are widely prescribed pharmacological treatments for smoking cessation. These treatments are only marginally effective in clinical populations but most preclinical studies show that they are effective in decreasing self-administration in rats on a group level. The present study investigated individual differences in responding to bupropion or varenicline in a preclinical model of long-access to nicotine (0.03 mg/kg/inf; 12 h/day) in female rats. Rats were first assessed for their individual economic demand for nicotine and for their individual performance in open field and elevated plus maze prior to nicotine access and during withdrawal. Rats were then tested for the acute effects of bupropion, varenicline, and yohimbine. We found that neither bupropion nor varenicline decreased responding for nicotine on test days. On the contrary, a moderate dose of bupropion (30 mg/kg) significantly increased responding for nicotine. We also found that rats with higher demand for nicotine were more sensitive to pretreatment with yohimbine which resulted in increased responding for nicotine during the dose-effect tests. Finally, we show that rats that had a higher demand for nicotine also were more persistent in seeking nicotine during extinction and reinstatement tests with nicotine or yohimbine as triggers. Our findings suggest that the length of access to daily nicotine may be an important factor underlying the response to pharmacological treatments like bupropion or varenicline. Future studies modeling chronic treatment approaches that include both sexes will be needed to further extend our findings.

The effect of varenicline on mood and cognition in smokers with HIV.

RATIONALE: Barriers to smoking cessation, including negative affect and cognitive dysfunction, may contribute to high smoking rates among people living with HIV/AIDS (PLWH). Varenicline may help PLWH quit smoking by improving mood and cognition, yet this has not been explored. OBJECTIVES: The goal of this study was to evaluate the effect of varenicline on mood and cognition among PLWH enrolled in a smoking cessation clinical trial. METHODS: In this secondary analysis of a varenicline trial (NCT01710137), we assessed mood (depression, anxiety) and cognition (attention, working memory) at weeks 0 (baseline), 1, 3, and 12 (end-of-treatment, EOT). Primary outcomes were changes in mood and cognition from baseline to EOT. Secondarily, mood and cognition were evaluated as predictors of biochemically confirmed 7-day point-prevalence abstinence at EOT. RESULTS: Overall, 173 subjects (87 varenicline, 86 placebo) were included. At EOT, varenicline reduced anxiety (P < 0.001), vs. placebo (P = 0.31; interaction P = 0.05). Across both treatment arms, reductions in anxiety from baseline to EOT were associated with a higher likelihood of abstinence (OR = 1.3, 95% CI 1.1 to 1.6, P = 0.01). There were no significant treatment by time interactions for cognition or depression. CONCLUSIONS: These data suggest that varenicline operates, at least in part, by reducing anxiety. Anxiety should be an intervention target for smokers with HIV interested in quitting.

Randomized Clinical Trials Investigating Innovative Interventions for Smoking Cessation in the Last Decade.

Every year, billions of dollars are spent treating smoking and related conditions, yet smoking-related morbidity and mortality continue to rise. There are currently only three FDA-approved medications for smoking cessation: nicotine replacement therapy, bupropion, and varenicline. Although these medications increase abstinence rates, most individuals relapse following treatment. This chapter reviews clinical trials published within the past 10 years investigating novel smoking cessation pharmacotherapies. Among these pharmacotherapies, some showed promising results, such as cytisine and endocannabinoid modulators, whereas others failed to produce significant effects. More research is needed to develop drugs that produce higher rates of long-term abstinence and to determine which subgroups of patients benefit from a given treatment.

Combined administration of varenicline and bupropion produces additive effects on accumbal dopamine and abolishes the alcohol deprivation effect in rats.

Alcohol use disorder (AUD) is detrimental to health and causes preterm death. Unfortunately, available pharmacological and nonpharmacological treatments have small effect sizes, and improved treatments are needed. Smoking and AUD share heritability and are pharmacologically associated, since drug-induced dopamine (DA) output in nucleus accumbens (nAc) involves nicotinic acetylcholine receptors (nAChRs) in both cases. Smoking therapy agents, such as the partial nAChR agonist varenicline or the DA/noradrenaline transporter inhibitor bupropion, could potentially also be used for AUD. To investigate this hypothesis, the effects of varenicline, bupropion, or a combination of the two on nAc DA levels, ethanol intake, and the alcohol deprivation effect (ADE) were examined. In vivo microdialysis showed that varenicline (1.5 mg/kg) and bupropion (2.5, 5, or 10 mg/kg) elevated nAc DA levels and that the combination produced additive effects. Five days treatment with varenicline, bupropion, or the combination did not suppress ethanol consumption, as compared with vehicle-treated control. However, combined administration of varenicline and bupropion completely blocked the ADE when readministering ethanol following 14 days of abstinence. Since ADE is considered highly predictive for the clinical outcome in man, our data suggest that the combination of varenicline and bupropion could be a promising treatment for AUD.

Pharmacogenomics of Nicotine Metabolism: Novel CYP2A6 and CYP2B6 Genetic Variation Patterns in Alaska Native and American Indian Populations.

INTRODUCTION: Alaska Native and American Indian (AN/AI) populations have higher tobacco use prevalence than other ethnic/racial groups. Pharmacogenetic testing to tailor tobacco cessation treatment may improve cessation rates. This study characterized polymorphic variations among AN/AI people in genes associated with metabolism of nicotine and drugs used for tobacco cessation. METHODS: Recruitment of AN/AI individuals represented six subgroups, five geographic subgroups throughout Alaska and a subgroup comprised of AIs from the lower 48 states living in Alaska. We sequenced the CYP2A6 and CYP2B6 genes to identify known and novel gain, reduced, and loss-of-function alleles, including structural variation (eg, gene deletions, duplications, and hybridizations). RESULTS: Variant allele frequencies differed substantially between AN/AI subgroups. The gene deletion CYP2A6*4 and reduced function CYP2A6*9 alleles were found at high frequency in Northern/Western subgroups and in Lower 48/Interior subgroups, respectively. The reduced function CYP2B6*6 allele was observed in all subgroups and a novel, predicted reduced function CYP2B6 variant was found at relatively high frequency in the Southeastern subgroup. CONCLUSIONS: Diverse CYP2A6 and CYP2B6 variation among the subgroups highlight the need for comprehensive pharmacogenetic testing to guide tobacco cessation therapy for AN/AI populations. IMPLICATIONS: Nicotine metabolism is largely determined by CYP2A6 genotype, and variation in CYP2A6 activity has altered the treatment success in other populations. These findings suggest pharmacogenetic-guided smoking cessation drug treatment could provide benefit to this unique population seeking tobacco cessation therapy.

The Novel CYP2A6 Inhibitor, DLCI-1, Decreases Nicotine Self-Administration in Mice.

During tobacco and e-cigarette use, nicotine is mainly metabolized in the human liver by cytochrome P450 2A6 (CYP2A6). Given that a slower CYP2A6 metabolism has been associated with less vulnerability to develop nicotine dependence, the current studies sought to validate a novel CYP2A6 inhibitor, (5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine (DLCI-1), for its effects on intravenous nicotine self-administration. Male and female mice were trained to self-administer nicotine across daily sessions. Once stable responding was achieved, DLCI-1 or vehicle control was administered prior to nicotine sessions. We found that the lower 25 mg/kg and moderate 50 mg/kg doses of DLCI-1 induced a significant decrease in nicotine intake for both males and females. DLCI-1 was further shown to be more effective than a moderate 1 mg/kg dose of bupropion on reducing nicotine intake and did not exert the adverse behavioral effects found with a high 75 mg/kg dose of bupropion. Although mice treated with DLCI-1 self-administered significantly less nicotine, similar nicotine-mediated behavioral effects on locomotion were observed. Together, along with the analysis of nicotine metabolites during self-administration, these findings support the contention that blocking hepatic nicotine metabolism would allow for similar activation of nicotinic acetylcholine receptors at lower nicotine doses. Moreover, these effects of DLCI-1 were specific to nicotine self-administration, as DLCI-1 did not result in any behavioral changes during food self-administration. Taken together, these studies validate DLCI-1 as a novel compound to decrease nicotine consumption, which may thereby promote tobacco and nicotine product cessation. SIGNIFICANCE STATEMENT: Current pharmacological approaches for nicotine and tobacco cessation have only been able to achieve limited efficaciousness in promoting long-term abstinence. In this work, we characterize the effects of a novel compound, (5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine (DLCI-1), which inhibits the main enzyme that metabolizes nicotine, and we report a significant decrease in intravenous nicotine self-administration in male and female mice, supporting the potential of DLCI-1 as a novel tobacco cessation pharmacotherapeutic.

Δ8 -Tetrahydrocannabivarin has potent anti-nicotine effects in several rodent models of nicotine dependence.

BACKGROUND AND PURPOSE: Both types of cannabinoid receptors-CB1 and CB2 -regulate brain functions relating to addictive drug-induced reward and relapse. CB1 receptor antagonists and CB2 receptor agonists have anti-addiction efficacy, in animal models, against a broad range of addictive drugs. Δ9 -Tetrahydrocannabivarin (Δ9 -THCV)-a cannabis constituent-acts as a CB1 antagonist and a CB2 agonist. Δ8 -Tetrahydrocannabivarin (Δ8 -THCV) is a Δ9 -THCV analogue with similar combined CB1 antagonist/CB2 agonist properties. EXPERIMENTAL APPROACH: We tested Δ8 -THCV in seven different rodent models relevant to nicotine dependence-nicotine self-administration, cue-triggered nicotine-seeking behaviour following forced abstinence, nicotine-triggered reinstatement of nicotine-seeking behaviour, acquisition of nicotine-induced conditioned place preference, anxiety-like behaviour induced by nicotine withdrawal, somatic withdrawal signs induced by nicotine withdrawal, and hyperalgesia induced by nicotine withdrawal. KEY RESULTS: Δ8 -THCV significantly attenuated intravenous nicotine self-administration and both cue-induced and nicotine-induced relapse to nicotine-seeking behaviour in rats. Δ8 -THCV also significantly attenuated nicotine-induced conditioned place preference and nicotine withdrawal in mice. CONCLUSIONS AND IMPLICATIONS: We conclude that Δ8 -THCV may have therapeutic potential for the treatment of nicotine dependence. We also suggest that tetrahydrocannabivarins should be tested for possible anti-addiction efficacy in a broader range of preclinical animal models, against other addictive drugs, and eventually in humans.

Smokers with opioid use disorder may have worse drug use outcomes after varenicline than nicotine replacement.

INTRODUCTION: Smokers with opioid use disorder (OUD) have little success with smoking cessation, possibly due to interactions between nicotine and opioid receptor systems. Smokers with OUD versus non-opioid substance use disorders (NOUD) have not been compared for response to smoking treatment. Data to make this comparison came from our previous study of 12 weeks (plus dose run-up) of varenicline (VAR) versus 12 weeks of nicotine patch (NRT), in a double-placebo design. METHODS: The current study reports secondary analyses comparing smokers with OUD (n = 47) and NOUD (n = 90) on pretreatment smoking, alcohol and drug use, intolerance of physical discomfort, smoking medication adherence, and 3- and 6-month smoking and substance use outcomes (by VAR versus NRT). RESULTS: Smokers with OUD did not differ on pretreatment alcohol or smoking measures while reporting significantly more drug use days. Smokers with OUD versus NOUD had significantly fewer days adherent to VAR or placebo capsules but not to patches, and were more tolerant of physical discomfort. While smoking and heavy drinking days at follow-ups did not differ by diagnosis, smokers with OUD had significantly more drug use days in months 4-6 when assigned to VAR (16.4 days) than to NRT (8.1 days). CONCLUSIONS: NRT might be a better choice than VAR for smokers with OUD due to lower adherence and more drug use days with VAR. However, this novel comparison of smoking pharmacotherapy response in smokers with OUD versus NOUD needs to be confirmed with larger numbers of participants.

The Effects of Transdermal Nicotine Patches on the Cardiorespiratory and Lactate Responses During Exercise from Light to Moderate Intensity: Implications for Exercise Prescription during Smoking Cessation.

Background and objectives: Exercise can help ease withdrawal symptoms of smokers. However, there is little information about the physiological responses, such as cardiorespiratory and lactate (La) responses, during exercise from light to moderate intensity combined with transdermal nicotine patches (TNPs) in smokers. This study aimed to investigate the effect of TNPs on the cardiorespiratory and La responses during exercise at light to moderate intensity. Materials and Methods: Fourteen young men (8 non-smokers, 6 current smokers) aged 20 to 26 years participated in this study. They performed an incremental graded submaximal exercise test using an electromagnetic cycle ergometer set from 30 to 210 W with (TNP condition) or without a TNP (control condition) in a random order. The TNP was applied to the left arm 8-10 h prior to starting the exercise to achieve the peak level of blood nicotine concentration. Heart rate (HR), rate of perceived exertion (RPE), oxygen consumption (VO2), ventilation (VE), and blood La at rest and during exercise were measured and analyzed. Results: The HR at rest was significantly higher in the TNP condition than in the control condition (TNP; 74.7 ± 13.8 bpm, control; 65.3 ± 10.8 bpm, p < 0.001). There was no interaction (condition × exercise intensity) between any of the variables, and VO2, VE, RPE, and La during exercise were not significantly different between the conditions. However, HR during exercise was 6.7 bpm higher on average in the TNP condition. Conclusions: The HR during exercise was greater at light to moderate intensity with a TNP. Our study results will guide clinicians or health professionals when prescribing exercise programs combined with TNPs for healthy young smokers.

Proactive text messaging (GetReady2Quit) and nicotine replacement therapy to promote smoking cessation among smokers in primary care: A pilot randomized trial protocol.

INTRODUCTION: Most smokers see a physician each year, but few use any assistance when they try to quit. Text messaging programs improve smoking cessation in community and school settings; however, their efficacy in a primary care setting is unclear. The current trial assesses the feasibility and preliminary clinical outcomes of text messaging and mailed nicotine replacement therapy (NRT) among smokers in primary care. METHODS: In this single-center pilot randomized trial, eligible smokers in primary care are offered brief advice by phone and randomly assigned to one of four interventions: (1) Brief advice only, (2) text messages targeted to primary care patients and tailored to quit readiness, (3) a 2-week supply of nicotine patches and/or lozenges (NRT), and (4) both text messaging and NRT. Randomization is stratified by practice and intention to quit. The text messages (up to 5/day) encourage those not ready to quit to practice a quit attempt, assist those with a quit date through a quit attempt, and promote NRT use. The 2-week supply of NRT is mailed to patients' homes. RESULTS: Feasibility outcomes include recruitment rates, study retention, and treatment adherence. Clinical outcomes are assessed at 1, 2, 6, and 12-weeks post-enrollment. The primary outcome is ≥1self-reported quit attempt(s). Secondary clinical outcomes include self-reported past 7- and 30-day abstinence, days not smoked, NRT adherence, and exhaled carbon monoxide. CONCLUSIONS: This pilot assesses text messaging plus NRT, as a proactively offered intervention for smoking cessation support in smokers receiving primary care and will inform full-scale randomized trial planning. TRIAL REGISTRATION: ClinicalTrials.govNCT03174158.

Ultrapotent chemogenetics for research and potential clinical applications.

Chemogenetics enables noninvasive chemical control over cell populations in behaving animals. However, existing small-molecule agonists show insufficient potency or selectivity. There is also a need for chemogenetic systems compatible with both research and human therapeutic applications. We developed a new ion channel-based platform for cell activation and silencing that is controlled by low doses of the smoking cessation drug varenicline. We then synthesized subnanomolar-potency agonists, called uPSEMs, with high selectivity for the chemogenetic receptors. uPSEMs and their receptors were characterized in brains of mice and a rhesus monkey by in vivo electrophysiology, calcium imaging, positron emission tomography, behavioral efficacy testing, and receptor counterscreening. This platform of receptors and selective ultrapotent agonists enables potential research and clinical applications of chemogenetics.