M5 muscarinic receptor knockout: Deficiency of M5Rs reduces drug-seeking behavior.

The five Muscarinic Acetylcholine (ACh) receptors are G-protein coupled receptors (M1R-M5R). M1R, M3R and M5R selectively couple to Gq/G11; M2R and M4R selectively couple to Gi/Go. M5R knockout mice are viable and fertile, and have no major morphological abnormalities.

M5 muscarinic ACh receptors are located in the central nervous system and may contribute to the cognitive-enhancing effects of ACh. M5R knockout mice show deficits in two hippocampus-dependent cognitive tasks, and exhibit reduced cerebral blood flow in the cerebral cortex and hippocampus, consistent with the observation that M5Rs mediate ACh-mediated dilation of cerebral blood vessels. M5R agonists or agonists for mixed M1/M5 receptors may be effective in the treatment of Alzheimer’s disease and related memory disorders. The M5R knockout mutation also appears to exert a stabilizing effect on sensorimotor gating in intact mice, which is decreased in schizophrenia. Analysis of M5R knockout mice also has shown that the lack of M5Rs reduces drug-seeking behavior.