Effects Of Varenicline Research Articles

Effects of varenicline on alcohol self-administration and craving in drinkers with depressive symptoms.

Varenicline (VAR) is approved to aid in smoking cessation and has been shown to be effective for reducing alcohol consumption in heavy drinkers. Little is known, however, about treatment moderators that may influence efficacy. The current study reanalyzed data from a human laboratory study (Verplaetse et al., 2016) to determine whether VAR was more effective at reducing alcohol use among drinkers reporting symptoms of depression. Participants were 60 adults meeting DSM-IV criteria for alcohol use disorders ( n = 60) who were randomly assigned to receive VAR (1 mg/day, 2 mg/day) or placebo. Following 7 days of medication pretreatment, participants attended a laboratory testing session. They provided self-reported ratings of alcohol craving and performed an ad libitum alcohol consumption task after receiving a priming dose of alcohol (target blood alcohol concentration = 0.030 g/dL). Higher blood VAR plasma levels were associated with less alcohol craving and less drinking among participants with more depressive symptoms. Among participants with fewer depressive symptoms, VAR was associated with more drinking during the ad libitum drinking task. These findings show that depression symptoms may be a moderator of VAR efficacy in alcohol users and provides evidence for the role of nAChRs in depression and alcohol use.

The effect of varenicline and nicotine patch on smoking rate and satisfaction with smoking: an examination of the mechanism of action of two pre-quit pharmacotherapies.

In recent years, there has been growing research interest in using nicotine replacement medications to aid smoking reduction prior to a quit attempt. Gaining a better understanding of how treatments influence smoking reduction may allow for better tailoring of treatments and, ultimately, better cessation outcomes. The objective of the current study was to test the effects of the pre-quit use of varenicline and nicotine patch on smoking rate and satisfaction with smoking. All participants were required to attend up to five study visit sections. Participants (n=213) who were interested in quitting were randomised (open-label) to receive either pre-quit patch or varenicline (both treatments started 2weeks prior to an assigned quit day, followed by 10weeks post-quit) or standard patch (10weeks starting from an assigned quit day). Participants used modified smartphones to monitor their smoking in real time for 4weeks. Participants in the two pre-quit treatment groups reported significant reductions in both their satisfaction with smoking (p<0.001) and smoking rate (p<0.001) from baseline to the end of pre-quit period; participants in the standard patch group did not. The observed reduction of smoking rate was associated with the satisfaction with smoking (p<0.01), although the mediation effect of satisfaction was small. Pre-quit treatment caused reductions in satisfaction with smoking and smoking rate. Satisfaction was associated with changes in smoking rate, but the relationship was weak. As such, monitoring reductions in satisfaction do not appear to be a viable method of evaluating responsiveness to treatment.

Varenicline enhances oxidized LDL uptake by increasing expression of LOX-1 and CD36 scavenger receptors through α7 nAChR in macrophages.

Varenicline is a widely used and effective drug for smoking cessation. It is a partial agonist of the α4β2 nicotinic acetylcholine receptor (nAChR) and full agonist of α7 nAChR. We have reported that varenicline aggravates formation of atherosclerotic plaques through α7 nAChR in apolipoprotein E knockout mice. However, little is known about its effects on macrophages in atherosclerotic plaques. Here, we ascertained whether varenicline promotes oxidized low-density lipoprotein (oxLDL) uptake in mouse peritoneal macrophages in vitro and clarified its mechanism. We investigated the effects of varenicline (1-10μM) on expression of scavenger receptors (lectin-like oxidized LDL receptor-1 (LOX-1), cluster of differentiation (CD) 36 and scavenger receptor class A (SR-A)) in RAW264.7 cells. Expression of protein and mRNA was determined by western blotting and real-time quantitative reverse transcription-polymerase chain reaction, respectively. Effects of varenicline (10μM) on oxLDL uptake were examined by counting the number of macrophages stained with oil red O and hematoxylin. Varenicline significantly increased expression of the protein and mRNA of LOX-1 and CD36, but not SR-A, in RAW264.7 cells, and increased oxLDL uptake in macrophages. These effects of varenicline were blocked significantly by an α7 nAChR antagonist, methyllycaconitine (MLA) (50nM), but not by an α4β2 nAChR antagonist, dihydro-β-erythroidine hydrobromide (DHβE) (1μM). These data suggest that varenicline promotes oxLDL uptake by upregulating expression of LOX-1 and CD36 through α7 nAChR in macrophages. We found that varenicline significantly activated extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor-kappa B (NF-κB) signaling pathways in RAW264.7 cells. This activation was blocked by MLA but not DHβE. Therefore, ERK1/2-NF-κB signaling pathway is highly likely to be responsible for varenicline-induced upregulation of LOX-1 and CD36 expression through α7 nAChR in macrophages. These processes probably contribute to varenicline-aggravated atherosclerotic plaque formation. Hence, an increased risk of cardiovascular events upon varenicline treatment could occur, and must be considered in patients (especially those suffering from cardiovascular diseases).

Varenicline provokes impulsive action by stimulating α4β2 nicotinic acetylcholine receptors in the infralimbic cortex in a nicotine exposure status-dependent manner

Higher impulsivity is a risk factor for criminal involvement and drug addiction. Because nicotine administration enhances impulsivity, the effects of stop-smoking aids stimulating nicotinic acetylcholine receptors (nAChRs) on impulsivity must be determined in different conditions. Our goals were 1) to confirm the relationship between varenicline, a stop-smoking aid and α4β2 nAChR partial agonist, and impulsivity, 2) to elucidate the mechanisms underlying the effects of varenicline, 3) to examine whether a low dose of varenicline that does not evoke impulsive action could block the stimulating effects of nicotine on impulsive action, 4) to determine whether the route of administration could modulate the effects of varenicline on impulsive action, and 5) to determine whether the effects of varenicline on impulsivity could be altered by smoking status. We used a 3-choice serial reaction time task to assess impulsivity and other cognitive functions in rats. Our findings are as follows: 1) acute subcutaneous (s.c.) injection of varenicline evoked impulsive action in a dose-dependent manner; 2) the effects of varenicline on impulsivity were blocked by the microinjection of dihydro-β-erythroidine, a α4β2 nAChR antagonist, into the infralimbic cortex; 3) the low dose of varenicline did not attenuate the effects of nicotine on impulsive action at all; 4) oral administration of varenicline evoked impulsive action in a similar manner to s.c. injection; and 5) the stimulating effects of varenicline on impulsive action were not observed in rats that received nicotine infusion for 8days or nicotine-abstinent rats after discontinuing infusion. Additionally, we found that oral varenicline administration enhanced attentional function whether nicotine was infused or not. Thus, although varenicline administration could be harmless to heavy smokers or ex-smokers, it could be difficult for non-smokers with respect to impulsivity, whereas it may be beneficial with respect to attentional function.

The contribution of α4β2 and non-α4β2 nicotinic acetylcholine receptors to the discriminative stimulus effects of nicotine and varenicline in mice.

The extent to which non-α4β2 versus α4β2* nAChRs contribute to the behavioral effects of varenicline and other nAChR agonists is unclear. The purpose of this study was to characterize the discriminative stimulus effects of varenicline and nicotine using various nAChR agonists and antagonists to elucidate possible non-α4β2 nAChR mechanisms. Separate groups of male C57BL/6J mice were trained to discriminate varenicline (3.2mg/kg) or nicotine (1mg/kg). Test drugs included mecamylamine; the nAChR agonists epibatidine, nicotine, cytisine, varenicline, and RTI-102; the β2-containing nAChR antagonist dihydro-β-erythroidine (DHβE); the α7 nAChR agonist PNU-282987; the α7 antagonist methyllycaconitine (MLA); the α3β4 antagonist 18-methoxycoronaridine (18-MC); and the non-nAChR drugs midazolam and cocaine. In nicotine-trained mice, maximum nicotine-appropriate responding was 95% nicotine, 94% epibatidine, 63% varenicline, 58% cytisine, and less than 50% for RTI-102, PNU-282987, midazolam, and cocaine. In varenicline-trained mice, maximum varenicline-appropriate responding was 90% varenicline, 86% epibatidine, 74% cytisine, 80% RTI-102, 50% cocaine, and 50% or less for nicotine, PNU-282987, and midazolam. Drugs were studied to doses that abolished operant responding. Mecamylamine antagonized the discriminative stimulus effects, but not the rate-decreasing effects, of nicotine and varenicline. DHβE antagonized the discriminative stimulus and rate-decreasing effects of nicotine but not varenicline in either the nicotine or varenicline discrimination assays. The discriminative stimulus, but not the rate-decreasing, effects of epibatidine were antagonized by DHβE regardless of the training drug. These results suggest that α4β2* nAChRs differentially mediate the discriminative stimulus effects of nicotine and varenicline, and suggest that varenicline has substantial non-α4β2 nAChR activity.

Varenicline improves motor and cognitive deficits and decreases depressive-like behaviour in late-stage YAC128 mice

ObjectiveStudies in the post mortem human brain and in genetic mouse model suggest that dysfunctional cholinergic neurotransmission, through a loss of agonist rather than receptors may be a significant contributing factor to HD pathology. If correct, pharmacological replacement may therefore be a potential treatment strategy. We have investigated whether chronic administration of the selective nicotinic partial agonist varenicline improved motor, cognitive and affective symptoms in a transgenic mouse model of Huntington's disease. MethodThe performance of 15 month old YAC128 mice and age-matched wild-type littermates was assessed in the rotarod, T-maze, novel object recognition, novelty suppressed feeding and forced swim tests prior to and after treatment with varenicline (5 mg/kg/day for 28 days via miniosmotic pump). Thymidine analogues, whilst DARPP32 and EM48 immunohistochemistry were used to assess the effect of varenicline on progenitor cell proliferation and survival, medium spiny neurons and aggregate formation respectively. ResultsChronic treatment with varenicline significantly improved motor coordination, delay-dependent memory and reduced depressive-like behaviour in late stage YAC128 mice. Varenicline also produced genotype-independent improvements in recognition memory and reduced anxiety. In addition, varenicline displayed anxiolytic effects and improved spatial memory in the absence of compromised function. Functional improvements were accompanied by neuropathological changes including increased aggregate formation, neuroprotection and increased progenitor cell proliferation and survival. InterpretationOur findings provide evidence that administration of an exogenous nicotinic agonist may be of clinical benefit in the treatment of late-stage Huntington's disease.

Therapeutic concentrations of varenicline in the presence of nicotine increase action potential firing in human adrenal chromaffin cells.

Varenicline is a nicotinic acetylcholine receptor (nAChR) agonist used to treat nicotine addiction, but a live debate persists concerning its mechanism of action in reducing nicotine consumption. Although initially reported as α4β2 selective, varenicline was subsequently shown to activate other nAChR subtypes implicated in nicotine addiction including α3β4. However, it remains unclear whether activation of α3β4 nAChRs by therapeutically relevant concentrations of varenicline is sufficient to affect the behavior of cells that express this subtype. We used patch-clamp electrophysiology to assess the effects of varenicline on native α3β4* nAChRs (asterisk denotes the possible presence of other subunits) expressed in human adrenal chromaffin cells and compared its effects to those of nicotine. Varenicline and nicotine activated α3β4* nAChRs with EC50 values of 1.8 (1.2-2.7)μM and 19.4 (11.1-33.9)μM, respectively. Stimulation of adrenal chromaffin cells with 10ms pulses of 300μM acetylcholine (ACh) in current-clamp mode evoked sodium channel-dependent action potentials (APs). Under these conditions, perfusion of 50 or 100 nM varenicline showed very little effect on AP firing compared to control conditions (ACh stimulation alone), but at higher concentrations (250nM) varenicline increased the number of APs fired up to 436±150%. These results demonstrate that therapeutic concentrations of varenicline are unlikely to alter AP firing in chromaffin cells. In contrast, nicotine showed no effect on AP firing at any of the concentrations tested (50, 100, 250, and 500nM). However, perfusion of 50nM nicotine simultaneously with 100nM varenicline increased AP firing by 290±104% indicating that exposure to varenicline and nicotine concurrently may alter cellular behavior such as excitability and neurotransmitter release.

The effects of varenicline on methamphetamine self-administration and drug-primed reinstatement in male rats

Methamphetamine (meth) addiction is a costly burden to both the individual user and society as a whole. Establishing effective pharmacotherapies to treat meth dependence is needed to help solve this health problem. The study reported herein examined the effects of varenicline, a partial α4β2 and full α7 nicotinic acetylcholine receptor agonist, on meth self-administration and reinstatement in male Sprague-Dawley rats. Following indwelling jugular catheter surgery, rats were either trained to self-administer meth or saline on a variable ratio (VR) 3 schedule of reinforcement. Self-administration sessions (2h duration; 19 total sessions) were conducted daily. The effect of varenicline pretreatment on meth and saline self-administration was then determined using a within-study design. All rats received varenicline (0.0, 0.3, 1.0, and 3.0mg/kg) prior to 4 different test sessions. Dose order was randomly assigned and each test was separated by 2 standard self-administration sessions to assess stability of responding. Fifteen extinction sessions (no meth available) followed the last test. Extinction was followed by meth-primed (0.3mg/kg IP) reinstatement tests to examine the effect of varenicline on meth-seeking behavior. All rats again received all doses of varenicline over 4 separate reinstatement tests performed on 4 consecutive days. Varenicline did not alter self-administration of meth or saline. Additionally, the 0.3 and 1.0 doses of varenicline non-specifically increased active lever responding during the reinstatement test sessions. This latter finding suggests that varenicline may increase relapse liability and should not be utilized as pharmacotherapy to treat meth dependence.

L-tetrahydropalmatine reduces nicotine self-administration and reinstatement in rats.

BackgroundThe negative consequences of nicotine use are well known and documented, however, abstaining from nicotine use and achieving abstinence poses a major challenge for the majority of nicotine users trying to quit. l-Tetrahydropalmatine (l-THP), a compound extracted from the Chinese herb Corydalis, displayed utility in the treatment of cocaine and heroin addiction via reduction of drug-intake and relapse. The present study examined the effects of l-THP on abuse-related effects of nicotine.MethodsSelf-administration and reinstatement testing was conducted. Rats trained to self-administer nicotine (0.03 mg/kg/injection) under a fixed-ratio 5 schedule (FR5) of reinforcement were pretreated with l-THP (3 or 5 mg/kg), varenicline (1 mg/kg), bupropion (40 mg/kg), or saline before daily 2-h sessions. Locomotor, food, and microdialysis assays were also conducted in separate rats.Results l-THP significantly reduced nicotine self-administration (SA). l-THP’s effect was more pronounced than the effect of varenicline and similar to the effect of bupropion. In reinstatement testing, animals were pretreated with the same compounds, challenged with nicotine (0.3 mg/kg, s.c.), and reintroduced to pre-extinction conditions. l-THP blocked reinstatement of nicotine seeking more effectively than either varenicline or bupropion. Locomotor data revealed that therapeutic doses of l-THP had no inhibitory effects on ambulatory ability and that l-THP (3 and 5 mg/kg) significantly blocked nicotine induced hyperactivity when administered before nicotine. In in-vivo microdialysis experiments, l-THP, varenicline, and bupropion alone elevated extracellular dopamine (DA) levels in the nucleus accumbens shell (nAcb).ConclusionsSince l-THP reduces nicotine taking and blocks relapse it could be a useful alternative to varenicline and bupropion as a treatment for nicotine addiction.Electronic supplementary materialThe online version of this article (doi:10.1186/s40360-016-0093-6) contains supplementary material, which is available to authorized users.

Attenuated nicotine-like effects of varenicline but not other nicotinic ACh receptor agonists in monkeys receiving nicotine daily.

Chronic treatment can differentially impact the effects of pharmacologically related drugs that differ in receptor selectivity and efficacy. The impact of daily nicotine treatment on the effects of nicotinic ACh receptor (nAChR) agonists was examined in two groups of rhesus monkeys discriminating nicotine (1.78mg·kg-1 base weight) from saline. One group received additional nicotine treatment post-session (1.78mg·kg-1 administered five times daily, each dose 2h apart; i.e. Daily group), and the second group did not (Intermittent group). Daily repeated nicotine treatment produced a time-related increase in saliva cotinine. There was no significant difference in the ED50 values of the nicotine discriminative stimulus between the Daily and Intermittent group. Mecamylamine antagonized the effects of nicotine, whereas dihydro-β-erythroidine did not. Midazolam produced 0% nicotine-lever responding. The nAChR agonists epibatidine, RTI-36, cytisine and varenicline produced >96% nicotine-lever responding in the Intermittent group. The respective maximum effects in the Daily group were 100, 72, 59 and 28%, which shows that the ability of varenicline to produce nicotine-like responding was selectively decreased in the Daily as compared with the Intermittent group. When combined with nicotine, both varenicline and cytisine increased the potency of nicotine to produce discriminative stimulus effects. Nicotine treatment has a greater impact on the sensitivity to the effects of varenicline as compared with some other nAChR agonists. Collectively, these results strongly suggest that varenicline differs from nicotine in its selectivity for multiple nAChR subtypes.

Effects of varenicline on adverse outcomes: an observational cohort study using electronic medical records

BackgroundRegulators have issued warnings about the potential adverse effects of the smoking cessation medication varenicline. However, there is little evidence of the long-term effects of varenicline when prescribed in everyday clinical practice. We aimed to investigate the association of varenicline and nicotine replacement therapy (NRT) with adverse outcomes when prescribed in primary care. MethodsUsing the Clinical Practice Research Datalink (CPRD), we conducted an observational cohort study of electronic medical records and linked mortality and hospital admission data of 126 718 primary care patients in the UK prescribed varenicline (41 742) and NRT (84 976). We used three approaches to overcome potential residual confounding: multivariable adjusted regression, propensity score matching, and instrumental variable regression. The exposure was first prescription of varenicline or nicotine replacement therapy. The primary outcome was all-cause mortality 2 years after first prescription. Secondary outcomes were mortality from cardiovascular and respiratory disease, all-cause hospital admission and for cardiovascular and respiratory disease, incident primary care diagnosis of myocardial infarction or chronic obstructive pulmonary disease, and frequency of primary care attendance. FindingsIn multivariable adjusted analysis, mortality was lower among patients prescribed varenicline than in those prescribed NRT (OR 0·78, 95% CI 0·69 to 0·87; p<0·0001), as was hospital admission (0·85, 0·83 to 0·88; p<0·0001). There were similar rates of incident myocardial infarction (0·92, 0·75 to 1·14) and chronic obstructive pulmonary disease (1·05, 0·96 to 1·16). Patients prescribed varenicline were 13·9 percentage points less likely to subsequently attend primary care (95% CI 11·8 to 16·0, p<0·0001). The instrumental variable analysis found little evidence of a substantial increase in risk of adverse outcomes of mortality (mean difference per 100 patients treated 0·50, 95% CI −0·50 to 1·50), hospital admission (−0·91, −3·64 to 1·81), myocardial infarction (0·42, −0·05 to 0·88), or chronic obstructive pulmonary disease (−0·21, −1·39 to 0·96). InterpretationThere was little evidence of a substantial increase in risk of adverse outcomes in patients prescribed varenicline as part of their standard clinical care. The regulatory warnings associated with varenicline do not accurately reflect the scientific evidence and should be reconsidered by policy makers and regulators. FundingThe research described in this paper was funded by the Medical Research Council (MR/N01006X/1), the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (project number 14/49/94). KHT is funded by a clinical lectureship award from the NIHR. RMM is supported by Cancer Research UK (programme grant C18281/A19169) (the Integrative Cancer Epidemiology Programme). TJ is supported by the NIHR Collaboration for Leadership in Applied Health Research and Care West, University Hospitals Bristol NHS Foundation Trust. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the abstract for submission.

Effectiveness of varenicline versus nicotine replacement therapy on long-term smoking cessation in primary care: a prospective, cohort study of electronic medical records

BackgroundNo studies have investigated the effectiveness of varenicline versus nicotine replacement therapy (NRT) on long-term (>24 months) smoking cessation in primary care, or whether its effectiveness is altered by socioeconomic status. We aimed to estimate the long-term effectiveness of varenicline on smoking cessation, and to determine whether the effectiveness of varenicline differs by socioeconomic status. MethodsWe conducted a prospective cohort study of electronic medical records within the Clinical Practice Research Datalink (CPRD), using three different analytical methods: multivariable logistic regression, propensity score matching, and instrumental variable analyses. Our sample comprised 220 136 patients who were prescribed either NRT (n=149 526) or varenicline (70 610) between Sept 1, 2006, and Sept 30, 2015, who attended 654 general practices in the UK. Primary outcome was smoking cessation at 2 year follow-up. The outcome and covariates were defined with validated code lists and algorithms. Socioeconomic status was defined with the Index of Multiple Deprivation (IMD). We used multiple imputation to impute missing values of body-mass index (13·6%) and IMD (0·1%). FindingsPatients prescribed varenicline were more likely than those prescribed NRT to successfully quit smoking after 2 years (odds ratio 1·26, 95% CI 1·23 to 1·29; p<0·0001); results from the propensity score matching were similar. The association persisted up to 4 years' follow-up. Instrumental variable analysis indicated that, for every 100 patients treated with varenicline rather than NRT, an additional 4·99 patients (95% CI 3·01 to 6·98, p<0·0001) would be expected to quit up to 2 years after treatment. On average patients had 2·6 smoking cessation prescriptions in the 2 years after first prescription. We found little evidence that the effectiveness of varenicline differed by socioeconomic status. InterpretationPatients prescribed varenicline in primary care were less likely to smoke after 2 years than were those prescribed NRT. This is the largest study to date, to our knowledge, to investigate the effectiveness of varenicline for smoking cessation when used in real-world primary care. Although our results could be subject to residual confounding, they are consistent with results from a network meta-analysis and large randomised controlled trial, and together could be used to update clinical guidelines on the use of varenicline for smoking cessation. FundingThis research was funded by the Medical Research Council (MRC) (MR/N01006X/1) and the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (project number 14/49/94). KHT is funded by a clinical lectureship award from the NIHR. RMM is supported by Cancer Research UK (programme grant C18281/A19169) (the Integrative Cancer Epidemiology Programme). TJ is supported by the NIHR CLAHRC West, University Hospitals Bristol NHS Foundation Trust. No funding body has influenced data collection, analysis, or interpretation.

The effect of varenicline on binge-like ethanol consumption in mice is β4 nicotinic acetylcholine receptor-independent

BackgroundOur laboratory has previously shown that the smoking-cessation agent varenicline, an agonist/partial agonist of α4β2*, α3β4*, α3β2*, α6β2* (* indicates the possibility of additional subunits) and α7 subunits of nicotinic acetylcholine receptors (nAChRs), reduces ethanol consumption in rats only after long-term exposure (12 weeks). As compounds having partial agonistic activity on α3β4* nAChRs were shown to decrease ethanol consumption in rodents, we assessed here the involvement of the β4 subunit in the effect of varenicline in the reduction of short- and long-term binge-like ethanol drinking in mice. MethodsWe used the well-validated drinking-in-the-dark (DID) paradigm to model chronic binge-like ethanol drinking in β4−/− and β4+/+ littermate mice and compare the effect of intraperitoneal injection of varenicline (2mg/kg) on ethanol intake following short- (4 weeks) or long-term (12 weeks) exposure. ResultsDrinking pattern and amounts of ethanol intake were similar in β4−/− and β4+/+ mice. Interestingly, our results showed that varenicline reduces ethanol consumption following short- and long-term ethanol exposure in the DID. Although the effect of varenicline on the reduction of ethanol consumption was slightly more pronounced in β4−/− mice than their β4+/+ littermates no significant differences were observed between genotypes. ConclusionIn mice, varenicline reduces binge-like ethanol consumption both after short- and long-term exposure in the DID and this effect is independent of β4 nAChR subunit.

Effects of varenicline on motor cortical plasticity in non-smokers with schizophrenia

BackgroundNicotinic acetylcholine receptors (nAChR) have been implicated in the pathophysiology of schizophrenia, and deficits in this system may contribute to high rates of cigarette smoking in this population. nAChR stimulation may modulate neuroplasticity, or long-term potentiation (LTP), which is a key mediator of cognitive performance. Varenicline is a nAChR partial agonist that may improve cognitive deficits in both smokers and non-smokers with schizophrenia; however, the mechanism by which varenicline alters cognition in schizophrenia remains unclear. Thus, the aim of this randomized, double-blind, placebo-controlled, crossover study was to determine the effects of varenicline on LTP-like plasticity indexed through transcranial magnetic stimulation (TMS) in non-smokers with schizophrenia. MethodsVarenicline (0.5mg BID × 5 doses) or placebo was administered to 9 non-smokers with schizophrenia and 10 non-smoker healthy subjects. LTP-like plasticity was induced by TMS and paired associative stimulation (PAS) at 0.1Hz to the left motor cortex and measured every 15min for two hours post-PAS. ResultsThere was a significant diagnosis × medication interaction on peak potentiation (F (3, 34)=6.04, p<0.02) and post-hoc analyses indicated that varenicline significantly increased LTP in schizophrenia and decreased LTP in healthy subjects. ConclusionsThese preliminary findings suggest that varenicline may produce differential effects in non-smoking schizophrenia compared to control subjects. Given the role of LTP in learning and memory, these observations may suggest the potential for varenicline in the treatment of cognitive deficits in patients with schizophrenia.

Varenicline improves motor and cognitive symptoms in early Huntington's disease.

The aim of this study was to describe the effects of varenicline, a smoking cessation aid that acts as a nicotinic agonist, on cognitive function in patients with early clinical Huntington’s disease (HD) who were current smokers. Three gene-positive patients transitioning to symptomatic HD were evaluated using the Unified Huntington’s Disease Rating Scale part I and III (motor and behavioral subscales) at baseline and after 4 weeks of treatment. Cognitive function was assessed using a touch screen computer-based neurocognitive test battery (IntegNeuro®). Varenicline (1 mg twice daily) significantly improved performance in executive function and emotional recognition tasks. Our case reports describe no clinically significant adverse effects and suggest that varenicline improves aspects of cognitive function in patients with early HD. A randomized controlled study is now underway.

Effects of varenicline on sympatho-vagal balance and cue reactivity during smoking withdrawal: a randomised placebo-controlled trial.

BackgroundVarenicline is an effective smoking cessation medication. Some concern has been raised that its use may precipitate adverse cardiovascular events although no patho-physiological mechanism potentially underlying such an effect has been reported. The aim of this study was to test the hypothesis that varenicline impacts on sympatho-vagal balance during smoking withdrawal.MethodsIn this randomised, placebo-controlled trial, muscle sympathetic nerve activity (MSNA), baroreflex sensitivity (BRS), heart rate, and blood pressure were assessed in 17 smokers four weeks before a quit attempt (baseline) and again on the third day of that quit attempt (acute smoking withdrawal).ResultsRegarding the primary endpoint of our study, we did not find a significant effect of varenicline compared to placebo on changes in MSNA burst incidence between baseline and acute smoking withdrawal (−3.0 ± 3.3 vs.−3.9 ± 5.0 bursts/100 heart beats; p = 0.308). However, heart rate and systolic blood pressure significantly decreased in the placebo group only, while no significant changes in these parameters were observed in the varenicline group. Exposure to smoking cues during acute withdrawal lead to a significant increase of heart rate in the placebo group, while heart rate decreased in the varenicline group, and the difference in these changes was significant between groups (+2.7 ± 1.0 vs.−1.8 ± 0.5 1/min; p = 0.002). In all 17 participants combined, a significant increase in heart rate during smoking cue exposure was detected in subjects who relapsed in the course of six weeks after the quit date compared to those who stayed abstinent (+2.5 ± 1.2 vs.−1.1 ± 0.7; p = 0.018). Six-week abstinence rates were higher in the varenicline group compared to placebo (88 vs. 22 % p = 0.015).ConclusionWe did not find evidence of adverse effects of varenicline on sympatho-vagal balance. Varenicline probably blunts the heart rate response to smoking cues, which may be linked to improved cessation outcome.

The nicotine + alcohol interoceptive drug state: contribution of the components and effects of varenicline in rats.

Nicotine and alcohol co-use is highly prevalent, and as such, individuals experience the interoceptive effects of both substances together. Therefore, examining sensitivity to a compound nicotine and alcohol (N + A) interoceptive cue is critical to broaden our understanding of mechanisms that may contribute to nicotine and alcohol co-use. This work assessed the ability of a N + A interoceptive cue to gain control over goal-tracking behavior and determined the effects of the α4β2 nicotinic partial agonist and smoking cessation compound varenicline on sensitivity to N + A. Two groups of male Long Evans rats were trained to discriminate N + A (0.4mg/kg nicotine + 1g/kg alcohol, intragastric gavage (IG)) from water under two different training conditions using a Pavlovian drug discrimination task. The effects of varenicline (0, 1, 3mg/kg, intraperitoneally (IP)) administered alone and on sensitivity to N + A and the components were determined. Under both training conditions, N + A rapidly gained control over behavior, with a greater contribution of nicotine to the N + A compound cue. Varenicline fully substituted for the N + A training dose, and varenicline (1mg/kg) enhanced sensitivity to the lowest N + A dose (0.1 N + 0.1 A). Given the high selectivity of varenicline for the α4β2 receptor, this finding suggests a functional role for α4β2 nicotinic acetylcholine receptors (nAChRs) in modulating sensitivity to N + A. The N + A compound cue is a unique cue that is modulated, in part, by activity at the α4β2 nAChR. These findings advance understanding of the interoceptive effects of nicotine and alcohol in combination and may have implications in relation to their co-use.

Effect of Varenicline Combined with High-Dose Alcohol on Craving, Subjective Intoxication, Perceptual Motor Response, and Executive Cognitive Function in Adults with Alcohol Use Disorders: Preliminary Findings.

Varenicline has been found to decrease alcohol-motivated behaviors. Recent warnings regarding aversive events associated with varenicline used in conjunction with alcohol warrant further investigation into the safety of the drug when combined with alcohol. The purpose of this preliminary investigation was to examine the effect of combining varenicline with a high, fixed dose of alcohol on subjective reactivity and cognitive function in adults with alcohol use disorders (AUDs). This double-blind, placebo-controlled preliminary investigation examined the effects of varenicline (0, 1, 2mg/d) on subjective reactivity, cognition, perceptual motor function, and physiologic reactivity to a fixed dose of alcohol (vs. nonalcohol control beverage) using an established laboratory paradigm in smokers and nonsmokers meeting criteria for AUDs (n=44). All participants had completed a parent varenicline study evaluating alcohol self-administration. Each subject completed 2 fixed-dose laboratory sessions assessing reactivity to a high-dose alcohol (0.08g/dl) or a nonalcoholic control beverage, order counterbalanced. Varenicline attenuated alcohol-related increases in subjective intoxication and alcohol-related decreases in executive cognitive function. At baseline, varenicline reduced alcohol craving and diastolic blood pressure, and increased associative learning, working memory, and perceptual motor function. Varenicline produced nonspecific effects on diastolic blood pressure and heart rate. Overall, there were few differences in effects between 1 and 2mg/d varenicline versus placebo. These preliminary results continue to support the safety and use of varenicline in combination with alcohol in individuals meeting criteria for AUDs.

Nicotine receptor partial agonists for smoking cessation.

Nicotine receptor partial agonists for smoking cessation.

Effect of Lowering the Dose of Varenicline on Alcohol Self-administration in Drinkers With Alcohol Use Disorders.

Varenicline (2 mg/d) has been shown to be efficacious in reducing alcohol consumption. A lower dose of varenicline may be effective in reducing alcohol use while minimizing the potential for side effects. This double-blind, placebo-controlled investigation examined the effect of varenicline (0, 1, 2 mg/d) on alcohol consumption in nontreatment-seeking adults meeting the Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DSM-IV) criteria for alcohol use disorders (N = 60). Following 7 days of medication pretreatment, participants were administered a low fixed dose of alcohol (0.3 g/dL), and subjective and physiologic responses were assessed. A 2-hour ad libitum alcohol self-administration period followed. We also explored relationships between plasma varenicline levels and consumption. Overall, frequency and severity of adverse events were minimal. The 1 mg/d dose reduced the frequency of insomnia compared with the 2 mg/d dose. The 2 mg/d varenicline dose versus placebo reduced alcohol craving and showed limited effect on reduced alcohol consumption. Alcohol craving and consumption did not differ between the 1 mg/d varenicline dose versus placebo. Trough varenicline plasma levels greater than or equal to 3 ng/mL were associated with reduced drinking and levels greater than or equal to 5 ng/mL were associated with reduced heavy drinking. Overall, we found no evidence supporting an effect of 1 mg/d varenicline on craving or consumption, suggesting that doses of varenicline less than 2 mg/d may not be effective in reducing alcohol-related outcomes. Importantly, results suggest that higher plasma levels of varenicline may be needed to maximize the effect of varenicline on alcohol consumption and should be investigated in drinkers meeting criteria for alcohol use disorders.