Neuroscience

Neuropeptide Y (NPY) regulates physiological processes via receptor subtypes (Y(1), Y(2), Y(4), Y(5), and y(6)). The Y(5) receptor is well known for its role in appetite. Based on expression in the limbic system, we hypothesized that the Y(5) receptor might also modulate stress sensitivity. We identified a novel Y(5) receptor-selective antagonist, Lu AA33810 [N-[[trans-4-[(4,5-dihydro[1]-benzothiepino[5,4-d]thiazol-2-yl)amino]cyclohexyl]methyl]-methanesulfonamide], that bound to cloned rat Y(5) receptors (K(i) = 1.5 nM) and antagonized NPY-evoked cAMP and calcium mobilization in vitro. Lu AA33810 (3-30 mg/kg p.o.) blocked feeding elicited by intracerebroventricular injection of the Y(5) receptor-selective agonist [cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]-hPancreatic Polypeptide in Sprague-Dawley rats. In vivo effects of Lu AA33810 were correlated with brain exposure > or = 50 ng/g and ex vivo Y(5) receptor occupancy of 22 to 95%. Lu AA33810 was subsequently evaluated in model...

Positron emission tomography (PET) imaging with the glucose analog 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F] FDG) has demonstrated clinical utility for the monitoring of brain glucose metabolism alteration in progressive neurodegenerative diseases. We examined dynamic [(18)F]FDG PET imaging and kinetic modeling of atlas-based regions to evaluate regional changes in the cerebral metabolic rate of glucose in the widely-used 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease. Following a bolus injection of 18.5 ± 1 MBq [(18)F]FDG and a 60-minute PET scan, image-derived input functions from the vena cava and left ventricle were used with three models, including Patlak graphical analysis, to estimate the influx constant and the metabolic rate in ten brain regions. We observed statistically significant changes in [(18)F]FDG uptake ipsilateral to the 6-OHDA injection in the basal ganglia, olfactory bulb, and amygdala regions; and these changes are of biological relevance to t...

Objective: The aim was to characterize Lu AA21004 in a number of preclinical models with predictive validity of anxiolytic and antidepressant activity. Lu AA21004 is a novel antidepressant with a unique pharmacological profile. Lu AA21004 is a 5-HT3 receptor antagonist (human (h)5-HT3 receptors Ki=4.5 nM), a 5-HT1A receptor agonist (h5-HT1A receptors: Ki=15 nM), and a 5-HT transport inhibitor (h5-HTT IC50=5.4 nM) that increases extracellular serotonin (5-HT), norepinephrine, dopamine, and acetylcholine levels in vivo in rat brain regions relevant to mood disorders. Methods: Antidepressant potential was assessed in the mouse forced swim and tail suspension tests, and anxiolytic potential was assessed using the mouse marble burying, rat conditioned fear, and rat social interaction tests. The behavioral responses in the rat were related to 5-HTT occupancy levels measured by ex vivo binding techniques using 3H-DASB as the radioligand. Results: Lu AA21004 produced dose-dependent antidepr...

Positron emission tomography (PET) imaging with the glucose analog 2-deoxy-2-[18F]fluoro-D-glucose ([18F] FDG) has demonstrated clinical utility for the monitoring of brain glucose metabolism alteration in progressive neurodegenerative diseases. We examined dynamic [18F]FDG PET imaging and kinetic modeling of atlas-based regions to evaluate regional changes in the cerebral metabolic rate of glucose in the widely-used 6-hydroxydopamine (6-OHDA) rat model of Parkinson’s disease. Following a bolus injection of 18.5 ± 1 MBq [18F]FDG and a 60-minute PET scan, image-derived input functions from the vena cava and left ventricle were used with three models, including Patlak graphical analysis, to estimate the influx constant and the metabolic rate in ten brain regions. We observed statistically significant changes in [18F]FDG uptake ipsilateral to the 6-OHDA injection in the basal ganglia, olfactory bulb, and amygdala regions; and these changes are of biological relevance to the disease. These experiments provide further validation for the use of [18F]FDG PET imaging in this model for drug discovery and development.