1. MK-7128, a novel CB1 receptor inverse agonist, improves scopolamine-induced learning and memory deficits in mice.
- Author
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Dillon GM, Lubbers LS, Ferguson MT, Lao JZ, Huang RR, Xiao JC, Fong TM, Hale JJ, Rupprecht K, Miao S, Rowe BA, Kornecook TJ, and Dodart JC
- Subjects
- Animals, Azetidines administration & dosage, Cerebral Cortex drug effects, Cerebral Cortex metabolism, Cognition Disorders drug therapy, Cognition Disorders physiopathology, Disease Models, Animal, Dose-Response Relationship, Drug, Hippocampus drug effects, Hippocampus metabolism, Male, Maze Learning drug effects, Memory Disorders physiopathology, Mice, Mice, Inbred C57BL, Oxadiazoles administration & dosage, Piperidines metabolism, Protein Binding, Pyrazoles metabolism, Scopolamine, Azetidines pharmacology, Drug Inverse Agonism, Memory Disorders drug therapy, Oxadiazoles pharmacology, Receptor, Cannabinoid, CB1 agonists
- Abstract
Cannabinoid receptors (CBRs) play an important role in a variety of physiological functions and have been considered drug targets for obesity and psychiatric disorders. In particular, the CB1R is highly expressed in brain regions crucial to learning and memory processes, and several lines of evidence indicate that pharmacological blockade of this receptor could have therapeutic applications in the treatment of cognitive disorders. In this study, we investigated whether MK-7128 (0.1, 0.3, and 1 mg/kg, orally), a novel and selective CB1R inverse agonist, could improve learning and memory deficits induced by scopolamine (1 mg/kg, subcutaneously) in mice. The investigators also assessed CB1R occupancy in the brain to ensure target engagement of MK-7128, and showed that MK-7128 significantly improved both Y-maze spontaneous alternation and object habituation performance in scopolamine-treated mice and inhibits the binding of radioiodinated AM251 in murine cortex and hippocampus. These data indicate that MK-7128 improves cognitive performance in a model of cholinergic hypofunction and suggest that efficacy is achieved at relatively low levels of CB1R occupancy in the brain. Our results extend earlier findings suggesting a role of CB1Rs in the modulation of memory processes and a potential therapeutic application for CB1R inverse agonists in cognitive disorders.
- Published
- 2011
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