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Facilitation of acetylcholine release and cognitive performance by an M(2)-muscarinic receptor antagonist in aged memory-impaired

Aged memory-impaired (AI) and unimpaired (AU) 24–25-month-old Long- Evans rats were used to investigate the integrity of various cholinergic markers during normal aging and to establish if alterations can possibly relate to cognitive disabilities. AI 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 various cortical and hippocampal areas between these two groups. Similarly, quantitative receptor autoradiography did not reveal significant differences in 3H-pirenzepine/muscarinic M1 and 3H- hemicholinium-3/high-affinity choline uptake binding sites in AI versus AU rats. In contrast, 3H-AF-DX 384/putative muscarinic M2 binding was significantly increased in certain cortical and hippocampal areas of the age-impaired animals. These increments were correlated with decreased in vivo acetylcholine (ACh) release capacity in the AI rats. Most interestingly, the muscarinic M2 antagonist BIBN-99 reversed, in a dose-dependent manner, the impaired ACh release as well as the cognitive deficits observed in the AI group. Similarly, BIBN-99 reversed scopolamine-induced amnesia in young animals. The efficacy of BIBN-99 likely relates to its antagonistic properties on negative muscarinic M2 autoreceptors that are apparently increased in the AI animals, leading to altered ACh 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.