FACILITATION OF ACETYLCHOLINE-RELEASE AND COGNITIVE PERFORMANCE BY ANM(2)-MUSCARINIC RECEPTOR ANTAGONIST IN AGED MEMORY-IMPAIRED RATS

Aged memory-impaired (Al) and unimpaired (AU) 24-25-month-old Long-Eva ns rats were used to investigate the integrity of various cholinergic markers during normal aging and to establish if alterations can possib ly relate to cognitive disabilities. Al and AU rats were classified on the basis of their performance in the Morris swim maze task. Choline acetyltransferase activity (ChAT) was not differentially altered in va rious cortical and hippocampal areas between these two groups. Similar ly, quantitative receptor autoradiography did not reveal significant d ifferences in H-3-pirenzepine/muscarinic M(1) and H-3-hemicholinium-3/ high-affinity choline uptake binding sites in Al versus AU rats. In co ntrast, H-3-AF-DX 384/putative muscarinic M(2) binding was significant ly increased in certain cortical and hippocampal areas of the age-impa ired animals. These increments were correlated with decreased in vivo acetylcholine (ACh) release capacity in the AI rats. Most interestingl y, the muscarinic M(2) antagonist BIBN-99 reversed, in a dose-dependen t manner, the impaired ACh release as well as the cognitive deficits o bserved in the AI group. Similarly, BIBN-99 reversed scopolamine-induc ed amnesia in young animals. The efficacy of BIBN-99 likely relates to its antagonistic properties on negative muscarinic M(2) autoreceptors that are apparently increased in the Al animals, leading to altered A Ch release. Taken together, these findings strengthen the role of ACh in learning and memory and may have implications for the treatment of degenerative disorders associated with impaired cholinergic functions, such as Alzheimer's disease.