期刊
JOURNAL OF NEUROSCIENCE
卷 22, 期 5, 页码 1709-1717出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.22-05-01709.2002
关键词
acetylcholine release; autoreceptors; knockout; mice; muscarinic receptors; oxotremorine; presynaptic; receptors
资金
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [Z01DK032003] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS030454] Funding Source: NIH RePORTER
- NINDS NIH HHS [R01 NS030454, NS30454] Funding Source: Medline
Forebrain muscarinic acetylcholine (ACh) receptors (mAChRs; M-1-M-5) are predicted to play important roles in many fundamental central functions, including higher cognitive processes and modulation of extrapyramidal motor activity. Synaptic ACh levels are known to be regulated by the activity of presynaptic muscarinic autoreceptors mediating inhibition of ACh release. Primarily because of the use of ligands with limited receptor subtype selectivity, classical pharmacological studies have led to conflicting results regarding the identity of the mAChR sub-types mediating this activity in different areas of the brain. To investigate the molecular identity of hippocampal, cortical, and striatal inhibitory muscarinic autoreceptors in a more direct manner, we used genetically altered mice lacking functional M-2 and/or M-4 mAChRs [knock-out (KO) mice]. After labeling of cellular ACh pools with [H-3] choline, potassium-stimulated [H-3] ACh release was measured in superfused brain slices, either in the absence or the presence of muscarinic drugs. The nonsubtype-selective muscarinic agonist, oxotremorine (0.1-10 muM), inhibited potassium-stimulated [H-3] ACh release in hippocampal, cortical, and striatal slices prepared from wildtype mice by up to 80%. This activity was totally abolished in tissues prepared from M-2-M-4 receptor double KO mice. Strikingly, release studies with brain slices from M-2 and M-4 receptor single KO mice indicated that autoinhibition of ACh release is mediated primarily by the M-2 receptor in hippocampus and cerebral cortex, but predominantly by the M-4 receptor in the striatum. These results, together with additional receptor localization studies, support the novel concept that autoinhibition of ACh release involves different mAChRs in different regions of the brain.
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