Alpha4beta2 Research Articles

Venomic study on cone snails (Conus spp.) from South Africa

From six Conus species (Conus coronatus, Conus lividus, Conus mozambicus f. lautus, Conus pictus, Conus sazanka, Conus tinianus) collected off the eastern coast of South Africa the venoms were analyzed using MALDI-TOF mass spectrometry. Between 56 and 151 molecular masses most in a range of 1000 to 2500 Da, were identified. Among the six venoms, between 0 and 27% (C. coronatus versus C. sazanka) of the peptide masses were found to be similar. In a study on venoms from 6 Conus species collected in the Philippines, the percentage of identical masses was between none and 9% only. The venoms from the South African Conus species antagonized the rat neuronal nicotinic acetylcholine receptors (nAChRs) α3β2, α4β2, and α7, except for C. coronatus venom that blocked the α4β2 and α7 nAChRs only. HPLC-fractionation of C. tinianus venom led to the isolation of a peptide that is active on all three receptor subtypes. It consists of 16 amino acid residues cross-linked by two disulfide bridges as revealed by de novo sequencing using tandem mass spectrometry: GGCCSHPACQNNPDYC. Posttranslational modifications include C-terminal amidation and tyrosine sulfation. The new peptide is a member of the α-conotoxin family that are competitive antagonists of nAChRs. Phylogenetic analysis of the 16S RNA from numerous Conus species has clarified the evolutionary position of endemic South African Conus species and provided the first evidence for their close genetic relationships.

Pharmacoeconomic Spotlight on Varenicline as an Aid to Smoking Cessation†

Varenicline (Chantix, Champix) is an orally administered alpha4beta2 nicotinic acetylcholine receptor partial agonist that is indicated as an aid to smoking cessation. Varenicline was an effective aid to smoking cessation and was generally well tolerated in clinical trials, although more data are needed regarding the potential for neuropsychiatric events. The costs associated with varenicline are offset by direct savings associated with the reduction in smoking-related diseases. Indeed, despite their limitations, available pharmacoeconomic analyses from numerous countries support the use of varenicline for 12 or 24 weeks as a cost-effective treatment relative to other smoking cessation therapies in smokers who wish to quit smoking. For example, in modelled cost-effectiveness analyses conducted from a healthcare payer perspective, 12 weeks' treatment with varenicline consistently dominated bupropion sustained release and nicotine replacement therapy, and was dominant over, or considered cost effective relative to, unaided cessation, brief counselling or nortriptyline, with regard to the incremental costs per quality-adjusted life-year or life-year gained.

Association between reduced Alpha4Beta2 nicotinic acetylcholine receptor availability and nonmotor symptoms in early drug naive Parkinson disease

Association between reduced Alpha4Beta2 nicotinic acetylcholine receptor availability and nonmotor symptoms in early drug naive Parkinson disease

Lower cortical Alpha4Beta2 nicotinic acetylcholine receptor binding and its relationship to cognitive dysfunction in early stage multiple sclerosis: A 2-[18F]F-A-85380 PET study

Lower cortical Alpha4Beta2 nicotinic acetylcholine receptor binding and its relationship to cognitive dysfunction in early stage multiple sclerosis: A 2-[18F]F-A-85380 PET study

α-Conotoxin AuIB Isomers Exhibit Distinct Inhibitory Mechanisms and Differential Sensitivity to Stoichiometry of α3β4 Nicotinic Acetylcholine Receptors

Non-native disulfide isomers of alpha-conotoxins are generally inactive although some unexpectedly demonstrate comparable or enhanced bioactivity. The actions of "globular" and "ribbon" isomers of alpha-conotoxin AuIB have been characterized on alpha3beta4 nicotinic acetylcholine receptors (nAChRs) heterologously expressed in Xenopus oocytes. Using two-electrode voltage clamp recording, we showed that the inhibitory efficacy of the ribbon isomer of AuIB is limited to approximately 50%. The maximal inhibition was stoichiometry-dependent because altering alpha3:beta4 RNA injection ratios either increased AuIB(ribbon) efficacy (10alpha:1beta) or completely abolished blockade (1alpha:10beta). In contrast, inhibition by AuIB(globular) was independent of injection ratios. ACh-evoked current amplitude was largest for 1:10 injected oocytes and smallest for the 10:1 ratio. ACh concentration-response curves revealed high (HS, 1:10) and low (LS, 10:1) sensitivity alpha3beta4 nAChRs with corresponding EC(50) values of 22.6 and 176.9 microM, respectively. Increasing the agonist concentration antagonized the inhibition of LS alpha3beta4 nAChRs by AuIB(ribbon), whereas inhibition of HS and LS alpha3beta4 nAChRs by AuIB(globular) was unaffected. Inhibition of LS and HS alpha3beta4 nAChRs by AuIB(globular) was insurmountable and independent of membrane potential. Molecular docking simulation suggested that AuIB(globular) is likely to bind to both alpha3beta4 nAChR stoichiometries outside of the ACh-binding pocket, whereas AuIB(ribbon) binds to the classical agonist-binding site of the LS alpha3beta4 nAChR only. In conclusion, the two isomers of AuIB differ in their inhibitory mechanisms such that AuIB(ribbon) inhibits only LS alpha3beta4 nAChRs competitively, whereas AuIB(globular) inhibits alpha3beta4 nAChRs irrespective of receptor stoichiometry, primarily by a non-competitive mechanism.

Interaction of Selective Serotonin Reuptake Inhibitors with Neuronal Nicotinic Acetylcholine Receptors

We compared the interaction of fluoxetine and paroxetine, two selective serotonin reuptake inhibitors (SSRIs), with the human (h) alpha4beta2, alpha3beta4, and alpha7 nicotinic acetylcholine receptors (AChRs) in different conformational states, using Ca(2+) influx, radioligand binding, and molecular docking approaches. The results established that (1) fluoxetine was more potent than paroxetine in inhibiting agonist-activated Ca(2+) influx on halpha4beta2 and halpha7 AChRs, whereas the potency of both SSRIs was practically the same in the halpha3beta4 AChR. [corrected] (2) SSRIs bind to the [(3)H]imipramine locus with a [corrected] higher affinity when the AChRs are in the desensitized states compared to the resting states. (3) The different receptor specificity for fluoxetine determined by their inhibitory potencies or binding affinities suggests different modes of interaction when the AChR is in the closed or activated state. (4) Neutral and protonated fluoxetine interacts with a binding domain located in the middle of the AChR ion channel. In conclusion, SSRIs inhibit the most important neuronal AChRs with potencies and affinities that are clinically relevant by binding to a luminal site that is shared with tricyclic antidepressants.

Effects of sazetidine-A, a selective α4β2 nicotinic acetylcholine receptor desensitizing agent on alcohol and nicotine self-administration in selectively bred alcohol-preferring (P) rats

Manipulations of nicotinic cholinergic receptors have been shown to influence both alcohol and nicotine intake. Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a novel compound that potently and selectively desensitizes alpha4beta2 nicotinic receptors with only modest receptor activation. The goal of the present study was to examine the effects of sazetidine-A on alcohol and nicotine self-administration in alcohol-preferring (P) rats. P rats were given the choice of water or alcohol. Once stable baselines were established, the acute (0, 0.1, 0.3, 1, and 3 mg/kg, s.c.) and chronic (3 mg/kg for 10 days) effects of sazetidine-A on alcohol intake were assessed. Naltrexone (2.5 mg/kg) served as a positive control. The effect of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on saccharin (0.2%) preference was also assessed. In addition, the acute effects of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on alcohol intake after alcohol deprivation were evaluated. In another experiment, the effects of sazetidine-A (0, 1, or 3 mg/kg) on i.v. nicotine self-administration in P and NP rats were assessed. Sazetidine-A caused a dose-dependent reduction in alcohol intake. Chronic sazetidine-A also effectively reduced alcohol intake until the seventh day of treatment, when partial tolerance appeared to develop. In the post-deprivation study, sazetidine-A significantly reduced alcohol intake and preference. Sazetidine-A at 3 mg/kg significantly reduced nicotine self-administration in both lines. Sazetidine-A significantly reduced alcohol and nicotine intake in P rats that self-administer higher levels of both drugs. Sazetidine-A may hold promise for the treatment of alcohol and nicotine addiction.

Activin A regulates trophoblast cell adhesive properties: implications for implantation failure in women with endometriosis-associated infertility

During implantation, the embryo adheres to the endometrium via cell adhesion molecules (CAMs) present on blastocyst trophectoderm and endometrial epithelial cells. CAMs, including integrins and extracellular matrix (ECM) ligands, are most likely regulated by hormones, cytokines and growth factors. We hypothesized first that activin A affects the adhesive properties of trophoblast cells and second that alterations in dimeric activin A levels in the uterine cavity could disrupt adhesion, thereby causing implantation failure. This study examined effects of activin A on trophoblast cell adhesion and measured activin A levels in secretory phase uterine washings from women with and without endometriosis (EOS). Activin receptor expression on trophoblast (HTR8) cells was examined by RT-PCR, and adhesive molecules measured by integrin antibody and cell-matrix adhesion assays. Dimeric activin A was measured (enzyme-linked immunosorbent assay) in uterine washings (14 controls and 23 EOS), and betaA-subunit localization was verified in endometrial tissues. Activin receptors are expressed by HTR8 cells. Activin A activated Smad2 in a concentration-dependent manner which was blocked by an activin receptor inhibitor (SB431542). Following activin A treatment (50 ng/ml for 24 h), trophoblast cell surface integrins alpha1 alpha2 alpha3 alpha5, beta1, beta2, beta4 and alphavbeta5 were decreased, as was cell binding to the ECM ligands, fibronectin, collagen IV and collagen I (P < 0.05). Activin A was detected in 56.5% of EOS and 21.4% of control washings, with measured levels from 42 to 8481 pg/ml (not significantly different). Decreased trophoblast CAM production and adhesion could be caused by dysregulated local activin A levels and may contribute to implantation failure. This could explain, in part, the infertility observed in women with EOS.

Varenicline and mecamylamine attenuate locomotor sensitization and cross-sensitization induced by nicotine and morphine in mice

The present study focused on the evaluation of behavioural sensitization and cross-sensitization induced by nicotine and morphine in mice. First, we revealed that after 9 days of nicotine administration (0.175 mg/kg, free base), every other day and following its 7-day withdrawal, challenge doses of nicotine (0.175 mg/kg) and morphine (5 mg/kg) induced locomotor sensitization in mice. When we examined the influence of varenicline, a partial alpha4beta2 nicotinic receptor agonist (0.5, 1 and 2 mg/kg) and mecamylamine (0.5, 1 and 2 mg/kg), a non-selective nicotinic receptor antagonist, we found that both agents attenuated the acquisition and expression of nicotine sensitization as well as locomotor cross-sensitization between nicotine and morphine. Our results indicate similar cholinergic mechanisms involved in the locomotor stimulant effects of nicotine and morphine in mice, and as such these data may suggest that nicotinic neurotransmission could be a potential target for developing pharmacotherapeutic strategies to treat and prevent nicotine and/or opioid addiction.

Varenicline does not increase serum BDNF levels in patients with nicotine dependence

Varenicline, alpha4beta2 nicotinic acetylcholine receptor (nAChR) partial agonist, is a new class of medications for treating nicotine dependence. As an alpha4beta2 nAChR partial agonist, varenicline serves to reduce nicotine withdrawal symptoms, while high-affinity binding of the agonist mitigates the reinforcing effects of smoking. In the present study, we compared serum brain-derived neurotrophic factor (BDNF) levels of nicotine dependence and nonsmokers, and we investigated changes in serum BDNF levels after 8 weeks of treatment with varenicline. Patients met the DSM-IV criteria for nicotine dependence. Both the Fagerström test for nicotine dependence (FTND) and the Tobacco Dependence Screener (TDS) were used. Serum BDNF levels and breath carbon monoxide (CO) levels were measured before and 8 weeks after varenicline treatment. Fourteen of 16 subjects (87.5%) stopped smoking within 12 weeks of varenicline treatment. Thirteen healthy nonsmokers who never had previously smoked were randomly selected as a control group. Serum BDNF levels of patients before treatment (4.8 +/- 3.8 ng/ml) were significantly lower than those in the control group (12.4 +/- 6.13 ng/ml). Serum BDNF levels had not increased from baseline (4.8 +/- 3.8 ng/ml) to 8 weeks after varenicline treatment (3.0 +/- 1.1 ng/ml) of patients. These results suggest that smoking might decrease serum BDNF levels and that treatment with varenicline for 8 weeks, combined with 12 weeks of not smoking, does not increase serum BDNF levels in smokers.

The neuronal nicotinic α4β2 receptor has a high maximal probability of being open

Background and purpose: A fundamental property of transmitter‐gated ion channels is the probability a channel will be open (Popen) when stimulated by a concentration of agonist that elicits a maximal response. This value is critical for interpreting steady‐state concentration–response relationships in terms of channel activation, and for understanding the actions of drugs that potentiate responses. We used analysis of non‐stationary noise to estimate the maximal probability the nicotinic α4β2 receptor is open.Experimental approach: HEK293 cells stably transfected to express human α4β2 nicotinic receptors were studied using whole‐cell voltage clamp. Nicotinic agonists (acetylcholine, nicotine, cytisine and 5‐iodo A‐85380) were applied, and the relationship between variance of the elicited whole‐cell current and mean current was analysed.Key results: The variance did not increase linearly with the mean current. For acetylcholine and nicotine the relationship between variance and mean indicates that the maximal Popen is greater than 0.8. The number of agonist‐activatable channels was estimated to be about 1000 per cell. The mean single channel conductance at −60 mV was indistinguishable when currents were elicited by acetylcholine (18 pS), nicotine (17 pS) or 5‐iodo A‐85380 (17 pS), whereas the value for cytisine was larger (24 pS).Conclusions and implications: The neuronal nicotinic α4β2 receptor has a maximal probability of being open that is greater than 0.8. This conclusion applies to the receptor containing three α4 and two β2 subunits (the low‐sensitivity stoichiometry), but may not apply to the receptor containing two α4 and three β2 subunits (the high‐sensitivity stoichiometry).This article is commented on by Papke, pp. 1903–1905 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476‐5381.2010.00868.x

Nicotine provokes impulsive-like action by stimulating α4β2 nicotinic acetylcholine receptors in the infralimbic, but not in the prelimbic cortex

Nicotine, a major addictive component of tobacco, has been suggested to provoke impulsivity by activating central alpha4beta2 nicotinic acetylcholine receptors (nAChRs). Although lesion studies have demonstrated the involvement of the medial prefrontal cortex (mPFC) in impulsive action, the precise brain sites responsible for nicotine-induced impulsive action have not been identified. Our goal was to determine whether alpha4beta2 nAChRs in the prelimbic cortex (PL) and/or infralimbic cortex (IL), which are subregions of the mPFC, mediate nicotine-induced impulsive-like action in the three-choice serial reaction time task (3-CSRTT). The 3-CSRTT is a simple version of five-choice serial reaction time task and a rodent model of impulsive action in which the animal is required to inhibit the response until a light stimulus is presented randomly in one of three holes. Following the completion of the training, rats were bilaterally injected with dihydro-beta-erythroidine (DHbetaE; 6 and 18 microg/side), a selective alpha4beta2 nAChRs antagonist, into the PL or IL before systemic injection of nicotine (0.2 mg/kg, salt, s.c.). Intra-IL DHbetaE infusions dose-dependently blocked nicotine-induced impulsive-like action, while infusions of DHbetaE into the PL failed to block the effects of nicotine on impulsive-like action. The present results suggest a critical role for alpha4beta2 nAChRs in the IL in mediating the effects of nicotine on impulsive-like action in the 3-CSRTT.

Effects of varenicline and mecamylamine on the acquisition, expression, and reinstatement of nicotine-conditioned place preference by drug priming in rats

Nicotine addiction is a chronic disorder characterized by a relatively high rate of relapse even after long period of abstinence. In the present study, we used the conditioned place preference (CPP) paradigm to investigate the establishment, extinction, reinstatement, and cross-reinstatement of nicotine-induced place conditioning in rats. First, we revealed that nicotine produced a place preference to the initially less-preferred compartment paired with its injections during conditioning (0.175 mg/kg, base, intraperitoneally (i.p.)). Once established, nicotine CPP was extinguished by repeated testing. Following this extinction phase, nicotine-experienced rats were challenged with nicotine (0.175 mg/kg, i.p.) or morphine (10 mg/kg, i.p.). These priming injections of both drugs induced a marked preference for the compartment previously paired with nicotine. Furthermore, given the important role of alpha4beta2 (a4b2) nicotinic receptor subtype in the acquisition and maintenance of nicotine dependence, we evaluated and compared the efficacy of varenicline, a partial a4b2 nicotinic receptor agonist (0.5, 1, and 2 mg/kg, subcutaneously (s.c.)), and mecamylamine (0.5, 1, and 2 mg/kg, s.c.), a non-selective nicotinic receptor antagonist, in blocking nicotine-induced CPP as well as reinstatement of nicotine CPP provoked by nicotine and morphine. It was shown that both nicotinic receptor ligands attenuated the acquisition and expression of nicotine CPP as well as the expression of reinstatement of nicotine CPP provoked by both drugs. Our results indicate similar cholinergic mechanisms, probably through the a4b2 receptors involved in the rewarding effects of nicotine and morphine in rats and may suggest that nicotinic receptors could be a potential target for developing pharmacotherapeutic strategies to treat and prevent nicotine and/or opioid addiction and relapse.

Non Smoking for Successful Aging: Therapeutic Perspectives

The smoke of cigarettes represents an important accelerator of the aging process, and there is no doubt that smoke is an important risk factor for many diseases, in particular for cardiovascular, neoplastic and respiratory diseases. Smoking plays an important role also in the development of other pathological conditions being particularly frequent in geriatric ages, such as dementia, osteoporosis, diabetes, erectile dysfunction, senile macular degeneration, nuclear cataract and alterations of skin. This means that smoke compromises not only life expectancy, but also the quality of the life, favoring the occurrence of non-autonomy. Non-smokers have a much higher life expectancy than smokers, and the suspension of smoking is accompanied, even in the elderly, by an increase in the survival time due to the reduction of smoke-induced biological damage. The first requirement of stopping smoking certainly is the motivation of the smoker himself to do this, since without this motivation any attempt is futile. Today numerous quitting strategies exist, either of pharmacological or non-pharmacological type, which are also advantageous for the elderly person. Approved pharmacological treatments include nicotine replacement therapies, bupropion, drugs targeting cannabinoid receptors and newer pharmacological approaches including the selective nicotinic partial agonists. Varenicline, an alpha4 beta2 nicotinic acetylcoline receptor partial agonist, is the most recently agent approved for smoking cessation. This drug works by reducing the strength of the smoker's urge to smoke and by relieving withdrawal symptoms. The most effective smoking cessation programs involve a combination of pharmacotherapy and behavioural and/or cognitive counselling to improve abstinence rates.

Varenicline

Varenicline (Chantix, Champix) is an orally administered alpha4beta2 nicotinic acetylcholine receptor partial agonist that is indicated as an aid to smoking cessation. Well designed clinical trials indicate that varenicline is an effective aid to smoking cessation. During the last 4 weeks of treatment, carbon monoxide-confirmed continuous abstinence rates were generally significantly higher with varenicline than with placebo, bupropion sustained release (SR) or nicotine replacement therapy. Varenicline also reduced cravings, the reinforcing effects of smoking and some withdrawal symptoms. Another well designed trial demonstrated that extending varenicline therapy by an additional 12 weeks helped maintain abstinence in individuals who had quit smoking. Varenicline was generally well tolerated in clinical trials; nausea, the most commonly occurring adverse event, diminished over time. More data are needed regarding the potential for neuropsychiatric events in varenicline recipients. Some of these events may be associated with nicotine withdrawal, rather than varenicline, although neuropsychiatric events have been observed in individuals who continued to smoke whilst receiving varenicline. In modelled cost-effectiveness analyses based on data from clinical trials in participants receiving smoking cessation therapy, 12 weeks' treatment with varenicline was predicted to be cost effective from a healthcare payer perspective in numerous countries. With regard to the incremental costs per QALY or life-year gained, 12 weeks' treatment with varenicline consistently dominated bupropion SR and nicotine replacement therapy and was dominant over or considered cost effective relative to unaided cessation, regular brief counselling or nortriptyline in analyses based on Markov models. In additional modelled analyses from a healthcare payer perspective, administering varenicline for an additional 12 weeks in participants who had successfully quit smoking was estimated to have acceptable incremental costs per QALY gained relative to varenicline for 12 weeks and to dominate other smoking cessation options. Moreover, in Swedish analyses that also included societal costs for production and consumption, the incremental cost per QALY gained for varenicline versus bupropion SR, and for an additional 12 weeks of varenicline therapy versus varenicline for 12 weeks only, was below commonly accepted thresholds of cost effectiveness. A US decision-analytic model from the perspective of various US health insurance plans demonstrated that, after 2 years, varenicline was predicted to dominate bupropion SR, in terms of the incremental cost per additional smoking cessation. Varenicline was also dominant or cost effective versus nicotine replacement therapy, and cost effective versus unaided cessation. Sensitivity analyses demonstrated that the results of cost-effectiveness studies were generally robust to plausible variations in key parameters. In conclusion, varenicline is an effective aid to smoking cessation. Varenicline was generally well tolerated in clinical trials, although more data are needed regarding the potential for neuropsychiatric events. The costs associated with varenicline are offset by direct savings associated with the reduction in smoking-related diseases. Despite their limitations, available pharmacoeconomic analyses from numerous countries support the use of varenicline for 12 or 24 weeks as a cost-effective treatment relative to other smoking cessation therapies in smokers who wish to quit smoking.

Enhancement of Attentional Performance by Selective Stimulation of α4β2* nAChRs: Underlying Cholinergic Mechanisms

Impairments in attention are a major component of the cognitive symptoms of neuropsychiatric and neurodegenerative disorders. Using an operant sustained attention task (SAT), including a distractor condition (dSAT), we assessed the putative pro-attentional effects of the selective alpha4beta2(*) nicotinic acetylcholine receptor (nAChR) agonist S 38232 in comparison with the non-selective agonist nicotine. Neither drug benefited SAT performance. However, in interaction with the increased task demands implemented by distractor presentation, the selective agonist, but not nicotine, enhanced the detection of signals during the post-distractor recovery period. This effect is consistent with the hypothesis that second-long increases in cholinergic activity ('transients') mediate the detection of cues and that nAChR agonists augment such transients. Electrochemical recordings of prefrontal cholinergic transients evoked by S 38232 and nicotine indicated that the alpha4beta2(*) nAChR agonist evoked cholinergic transients that were characterized by a faster rise time and more rapid decay than those evoked by nicotine. Blockade of the alpha7 nAChR 'sharpens' nicotine-evoked transients; therefore, we determined the effects of co-administration of nicotine and the alpha7 nAChR antagonist methyllycaconitine on dSAT performance. Compared with vehicle and nicotine alone, this combined treatment significantly enhanced the detection of signals. These results indicate that compared with nicotine, alpha4beta2(*) nAChR agonists significantly enhance attentional performance and that the dSAT represents a useful behavioral screening tool. The combined behavioral and electrochemical evidence supports the hypothesis that nAChR agonist-evoked cholinergic transients, which are characterized by rapid rise time and fast decay, predict robust drug-induced enhancement of attentional performance.

Efficacy and safety of varenicline for smoking cessation in patients with cardiovascular disease: a randomized trial.

Smoking cessation is a key component of secondary cardiovascular disease prevention. Varenicline, a partial alpha4beta2 nicotinic acetylcholine receptor agonist, is effective for smoking cessation in healthy smokers, but its efficacy and safety in smokers with cardiovascular disease are unknown. A multicenter, randomized, double-blind, placebo-controlled trial compared the efficacy and safety of varenicline with placebo for smoking cessation in 714 smokers with stable cardiovascular disease. Participants received varenicline (1 mg twice daily) or placebo, along with smoking-cessation counseling, for 12 weeks. Follow-up lasted 52 weeks. The primary end point was carbon monoxide-confirmed continuous abstinence rate for weeks 9 through 12 (last 4 weeks of treatment). The continuous abstinence rate was higher for varenicline than placebo during weeks 9 through 12 (47.0% versus 13.9%; odds ratio, 6.11; 95% confidence interval [CI], 4.18 to 8.93) and weeks 9 through 52 (19.2% versus 7.2%; odds ratio, 3.14; 95% CI, 1.93 to 5.11). The varenicline and placebo groups did not differ significantly in cardiovascular mortality (0.3% versus 0.6%; difference, -0.3%; 95% CI, -1.3 to 0.7), all-cause mortality (0.6% versus 1.4%; difference, -0.8%; 95% CI, -2.3 to 0.6), cardiovascular events (7.1% versus 5.7%; difference, 1.4%; 95% CI, -2.3 to 5.0), or serious adverse events (6.5% and 6.0%; difference, 0.5%; 95% CI, -3.1 to 4.1). As a result of adverse events, 9.6% of varenicline and 4.3% of placebo participants discontinued study drug. Varenicline is effective for smoking cessation in smokers with cardiovascular disease. It was well tolerated and did not increase cardiovascular events or mortality; however, trial size and duration limit definitive conclusions about safety. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov/ct2/show/NCT00282984. Unique identifier: NCT00282984.

Nicotinic 123I-5IA-85380 Single Photon Emission Computed Tomography as a Predictor of Cognitive Progression in Alzheimer's Disease and Dementia With Lewy Bodies

To investigate normalized I-5-Iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) single photon emission computed tomography (SPECT) imaging, a marker for the alpha4beta2 nicotinic receptor, as a predictor of cognitive progression in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Thirty-one patients with dementia (16 patients with AD and 15 patients with DLB) underwent I-5IA-85380 SPECT scanning. Image analysis was performed using statistical parametric mapping (SPM2), which involved spatial preprocessing of scans to standard Montreal Neurological Institute space and intensity normalization of each image to its mean global brain activity. Regression analysis revealed that reduced normalized I-5IA-85380 uptake in left superior, middle, and inferior frontal gyri and prepost central and anterior cingulate regions significantly correlated with decline in executive function in a pooled group comprising AD and DLB. The findings, although preliminary, suggest that the cholinergic system may be more involved in neurodegenerative processes affecting some cognitive processes more than others, as such, this procedure may be useful for increased understanding of the pathophysiological mechanisms responsible for neurodegeneration.

Treating the Cognitive Deficits of Schizophrenia with Alpha4Beta2 Neuronal Nicotinic Receptor Agonists

Schizophrenic patients exhibit debilitating impairments of intellectual function. Typical and atypical antipsychotic medications are largely ineffective at treating the cognitive deficits of schizophrenia (CDS), and efforts to discover compounds that treat these symptoms are ongoing. Considerable tobacco use in schizophrenic patients, genetic linkage, and receptor binding studies suggest the involvement of nicotinic acetylcholine receptors (nAChRs) in schizophrenia. Neuronal alpha4beta2 nAChRs are widely distributed in the mammalian brain, and are implicated in normal cognitive functioning in animal models. Ligands of various selectivity and potency have been used to study the role of the alpha4beta2 subtype in schizophrenia. For instance, studies in rodents show that alpha4beta2 agonists improve sensory gating, an information processing function that is deficient in schizophrenia. Pharmacological studies in animals also suggest that alpha4beta2 nAChRs are involved in other cognitive domains that are impaired in schizophrenia, including speed of processing, working memory, visual learning and memory, and social cognition. The non-selective nAChR agonist nicotine has been shown to improve CDS in several human clinical studies, and recent trials have been undertaken to evaluate the efficacy of more alpha4beta2 selective compounds. It remains to be determined whether alpha4beta2 agonists will provide greater efficacy than nicotine for CDS or reducing tobacco use in patients. Pre-clinical evidence to date suggests that agonists of the nicotinic alpha4beta2 subtype could be useful in improving cognitive function in schizophrenic patients.

The Human Neuronal Nicotinic α4β2 Receptor has a High Maximal Probability of Being Open

Studies of the functional properties of the nicotinic α4β2 receptor have been hampered by the facts that the receptors desensitize rapidly and extensively even to low concentrations of agonist, and the receptors “run down” rapidly upon patch excision. We have analyzed macroscopic (whole cell) responses of HEK cells stably transfected with human α4 and β2 subunits using nonstationary noise analysis. The variance does not increase linearly with the mean current, and even decreases for large responses evoked by acetylcholine or nicotine. The maximal response to ACh or nicotine has an estimated open probability of about 0.7. The estimated average single channel chord conductances (−60 mV) are: ACh 18 ± 6 pS (mean ± SD) and nicotine 17 ± 5 pS. The selective agonist 5-Iodo A85380 has a similar single channel conductance (17 ± 2 pS), whereas the agonist cytisine has a larger average estimated conductance (24 ± 4 pS). The estimated numbers of channels activated by ACh or nicotine are about 1000 - 2000 per cell, which is lower than the estimated numbers of surface receptors per cell (about 15,000; Zhang and Steinbach, Brain Res. 959:98 2003). These results demonstrate that the full agonists ACh and nicotine are efficacious agonists at this receptor. Supported by NIH NS 22356.