Effects of varenicline on alpha4-containing nicotinic acetylcholine receptor expression and cognitive performance in mice

• Published in: Neuropharmacology 2016-08, Vol.107, p.100-110
• Main Authors: Lange-Asschenfeldt, Christian, Schäble, Sandra, Suvorava, Tatsiana, Fahimi, Ehsan Gholamreza, Bisha, Marion, Stermann, Torben, Henning, Uwe, Kojda, Georg
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Brain - drug effects; Brain - metabolism; Cell Line; Cognition - drug effects; Cognition - physiology; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Male; Memory Disorders - drug therapy; Memory Disorders - metabolism; Mice, Inbred C57BL; Nootropic Agents - pharmacology; Novel object recognition; Protein upregulation; Receptors, Nicotinic - metabolism; Recognition (Psychology) - drug effects; Recognition (Psychology) - physiology; RNA, Messenger - metabolism; Scopolamine Hydrobromide; Scopolamine-induced memory impairment; Varenicline; Varenicline - pharmacology; α4β2 nicotinic acetylcholine receptor
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2016.03.025

Nicotinic acetylcholine receptor (nAChR) subtypes containing the α4 subunit, particularly α4β2 nAChRs, play an important role in cognitive functioning. The impact of the smoking cessation aid varenicline, a selective partial α4β2 nAChR agonist, on (1) changes of central protein and mRNA expression of this receptor and (2) on memory deficits in a mouse model of cognitive impairment was investigated. Protein and mRNA expression of both the α4 and β2 receptor subunits in mouse brain endothelial and hippocampal cells as well as hippocampus and neocortex tissues were determined by western blot and realtime PCR, respectively. The β2 antibody showed low specificity, though. Tissues were examined following a 2-week oral treatment with various doses of varenicline (0.01, 0.1, 1, 3 mg/kg/day) or vehicle. In addition, episodic memory of mice was assessed following this treatment with an object recognition task using (1) normal mice and (2) animals with anticholinergic-induced memory impairment (i.p. injection of 0.5 mg/kg scopolamine). Varenicline dose-dependently increased protein expression of both the α4 and β2 subunit in cell cultures and brain tissues, respectively, but had no effect on mRNA expression of both subunits. Scopolamine injection induced a significant reduction of object memory in vehicle-treated mice. By contrast, cognitive performance was not altered by scopolamine in varenicline-treated mice. In conclusion, a 2-week oral treatment with varenicline prevented memory impairment in the scopolamine mouse model. In parallel, protein, but not mRNA expression was upregulated, suggesting a posttranscriptional mechanism. Our findings suggest a beneficial effect of varenicline on cognitive dysfunction. •Varenicline increases α4 and β2 nAChR subunit protein in neuronal cell cultures.•Varenicline increases α4 and β2 nAChR subunit protein in brain vascular endothelium.•Varenicline upregulates α4β2 nAChR subunit protein in mouse neocortex and hippocampus.•Varenicline does not influence α4β2 nAChR mRNA in mouse neocortex and hippocampus.•Varenicline provides protection against scopolamine-induced memory deficits in mice.