Imaging [18F]FDG PET/CT pilot study of nicotinic acetylcholinergic receptor α2 knock-out mice and α2 hypersensitive mice compared to control mice: Male-female differences and nicotine effects

Nicotinic acetylcholinergic receptors (nAChRs), comprising of α and β subunits are present in the brain and whole body. The less abundant α2-subunit is a fast-acting receptor subtype and plays an important role in cognition and learning. To understand cellular functional consequences, this study evaluated glucose metabolism using [18F]FDG PET/CT in α2 knockout (α2KO) and α2 hypersensitive (α2HS) mice. Control (CN; 4M, 3F), α2 knockout (α2KO; 4M, 4F) and α2 hypersensitive (α2HS; 4M,4F), 12-16 month old mice were used. Mice were fasted and injected with [18F]FDG (3-5 MBq) while awake. After 40 minutes they underwent whole body PET/CT. On a separate day, nicotine challenge [18F]FDG studies were done. Reconstructed images were analyzed to obtain standard uptake values (SUV) of [18F]FDG in brain and interscapular brown adipose tissue (IBAT). Statistical analysis was performed comparing the three groups of mice. The α2HS male mice exhibited the largest brain increase in [18F]FDG compared to α2KO male mice. The rank order of brain [18F]FDG uptake in the three groups: α2HS♂ > CN♂ > α2KO♂ > CN♀= = α2KO♀ ≥ α2HS♀. Nicotine treatment reduced brain [18F]FDG uptake in all mice. Females had lower [18F]FDG uptake compared to males and were less sensitive to α2 nAChR. In the case of IBAT, α2KO mice had significantly higher baseline [18F]FDG uptake compared to the other two groups: α2KO♂ > α2KO♀ > α2HS♀ > α2HS♂ > CN♀ > CN♂. Nicotine decreased IBAT in α2KO mice rather than increase as observed in CN and α2HS mice.This preliminary study shows that α2 nAChRs play a significant role in brain activation as exhibited by the increase in [18F]FDG in α2HS mice. In the absence of regulatory control by the α2 nAChR, the α2KO mice IBAT exhibited higher [18F]FDG uptake compared to controls and α2HS mice. Female mice were less affected by nicotine compared to the male mice.