Pharmacological profile of the α4β2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid

Hoestgaard-Jensen

Journal of Biological Chemistry

2013

Background: Inefficient functional receptor expression in heterologous expression systems has hampered investigations of ␣6* nAChRs. Results: Determinants in the ␣6 subunit for ␣6␤4* functionality have been delineated. Conclusion: Phe 223 and the intracellular loop in ␣6 are molecular impediments to functional ␣6␤4* nAChR expression in vitro. Significance: The molecular basis for the inefficient functional expression of ␣6␤4* nAChRs in vitro has been elucidated.

Section: Journal Of Biological Chemistry 33711supporting

confidence: 89%

Elucidation of Molecular Impediments in the α6 Subunit for in Vitro Expression of Functional α6β4* Nicotinic Acetylcholine Receptors

Hoestgaard-Jensen

Journal of Biological Chemistry

2013

“…Using the mean 90% lower limit for B V /B max of 89% and the mean plasma varenicline concentration for these subjects of 1.4 ng/ml, we have K V p0.18 ng/ml (90%) or equivalently K V o0.49 nM (90%). This value is compatible with published in-vitro values for human cortex (0.15 nM) and human a4b2* nAChRs in HEK cells (0.11 nM) (Rollema et al, 2007). The percentage occupancies by brain region for smoking to satiety during the placebo scan are also given in Tables 1 and 2.…”

Section: Pet Findingssupporting

confidence: 88%

A Single Administration of Low-Dose Varenicline Saturates α4β2* Nicotinic Acetylcholine Receptors in the Human Brain

Lotfipour

Mandelkern

Alvarez-Estrada

et al. 2012

Neuropsychopharmacol

The primary objective of this project was to determine the a4b2* nicotinic acetylcholine receptor (nAChR) occupancy in human brain of a single low dose of varenicline (0.5 mg), and to explore the relationship between receptor occupancy by varenicline and tobacco withdrawal symptoms (*denoting other putative nAChR subunits). Otherwise healthy smokers (n ¼ 9) underwent two positron emission tomography (PET) sessions with the selective a4b2* radioligand 2-FA. For the PET sessions, participants received either a low dose of varenicline (0.5 mg) or matching placebo pill (double-blind, random order) before imaging. For both sessions, participants received bolus plus continuous infusions of 2-FA, were scanned for 1 h after allowing the radiotracer to reach a steady state, smoked to satiety, and were scanned for 2 more hours. We estimated the fractional receptor occupancy by a single dose of varenicline (0.5 mg) and the corresponding varenicline dissociation constant (K V ), along with the effect of low-dose varenicline, pill placebo, and smoking-to-satiety on withdrawal rating scales. The data are compatible with 100% occupancy of a4b2* nAChRs by a single dose of varenicline, with a 90% lower confidence limit of 89% occupancy for the thalamus and brainstem. The corresponding 90% upper limit on effective K V with respect to plasma varenicline was 0.49 nM. Smoking to satiety, but not low-dose varenicline, significantly reduced withdrawal symptoms. Our findings demonstrate that low-dose varenicline results in saturation of a4b2* nAChRs in the thalamus and brainstem without reducing withdrawal symptoms.

“…Smith et al (2009) found significant improvements in an open label study (N ¼ 12) in schizophrenia in some areas of cognition, particularly in the areas of verbal learning and memory. Others have also reported cognitive improvements in non-psychiatric populations in attention (Patterson et al, 2009) and working memory (Loughead et al, 2010;Patterson et al, 2009) that are similar to what is observed in animal studies (Rollema et al, 2007). Also a recently published double-blind trial (Hong et al, 2011) found that varenicline significantly reduced P50 sensory gating deficits in non-smokers and reduced startle reactivity and improved executive function regardless of smoking status.…”

Section: Clinical and Safety Datamentioning

confidence: 52%

“…Varenicline is a partial agonist with 45% of nicotine's maximal efficacy at a4b2 nAChRs (Rollema et al, 2007) and stimulates dopamine release from rat nucleus accumbens (Coe et al, 2005), which is mediated via interactions with a4b2 nAChRs in the ventral tegmental area, similar to nicotine-evoked DA release (Maskos et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Adjunctive Varenicline Treatment with Antipsychotic Medications for Cognitive Impairments in People with Schizophrenia: A Randomized Double-Blind Placebo-Controlled Trial

Shim

Jung

Jung³

et al. 2011

Neuropsychopharmacol

The aim of this study is to examine the effects of treatment with varenicline, a partial agonist at the a4b2 and full agonist at the a7 nicotine acetylcholine receptor, on cognitive impairments in people with schizophrenia. In all, 120 clinically stable people with schizophrenia participated in randomized, double-blind, placebo-controlled 8-week trial. Antipsychotic and concomitant medication doses remained fixed throughout the study. Varenicline was titrated up to 1 mg twice daily for weeks 2-8. Neuropsychological, clinical, and safety assessments were administered at baseline and weeks 1, 2, 4, and 8. In the primary analyses of neurocognitive differences at week 8, no varenicline-placebo differences were significant. In secondary longitudinal analyses, varenicline improved compared with placebo on the Digital Symbol Substitution Test (p ¼ 0.013) and the Wisconsin Card Sorting Test non-perseverative errors (p ¼ 0.043). Some treatment effects were different between smokers and non-smokers. In smokers, Continuous Performance Test hit reaction time (p ¼ 0.008) and Stroop Interference (p ¼ 0.004) were reduced for varenicline compared with placebo, while there were no treatment differences in non-smokers. No significant treatment main effects or interactions were noted for total scores on the Positive and Negative Syndrome Scale or the Scale for the Assessment for Negative Symptoms. Our findings suggest beneficial effects of adjunctive varenicline treatment with antipsychotics for some cognitive impairments in people with schizophrenia. In some cases, effects of treatment varied between smokers and non-smokers. Further study is required to assess the functional significance of these changes.