The influence of aging on brain muscarinic receptors in the rat

Abstract

Cognitive dysfunction is a dominant symptom that is generally reported in elderly as well as in Alzheimer's disease patients. The decline of such function is not recognized only in human beings but also in non-human mammalian species such as mice, rats, and monkeys. To explain this abnormality, several neurotransmitter systems have been demonstrated to decline accompanying the aging process and also they are postulated to play an important roles in the memory process, such as cholinergic, dopaminergic and noradrenergic system. However, a large number lines of evidence supported that the central cholinergic system especially in basal forebrain plays a pivotal role in memory function. These studies were designed to answer questions related to the effects of aging on the muscarinic receptor levels as well as its responsiveness upon the receptor stimulation. Fisher 344 rats were utilized as the study model since a large number of behavioral lines of evidence reported that the aged animals show a memory impairment similar to those in old humans. In this study, it is clear that there are age-associated specific alterations in the density of cell surface muscarinic receptors rather than the total receptors without changing their affinities in certain brain areas such as striatum and cerebral cortex. However, the alterations in receptor number is not associated with changes in the proportion as well as the affinities of pirenzepine-high affinity (M{dollar}\sb1{dollar}) and -low affinity (M{dollar}\sb2{dollar}: old nomenclature) in striatum, hippocampus and cerebral cortex with advancing age. In addition, the allosteric sites which are modulated by gallamine are not disturbed during the aging process. Furthermore, age-related changes in two main second messenger systems of muscarinic receptors such as the inhibition of adenylate cyclase (which may be linked to acetylcholine release) and PI hydrolysis (thought to play a pivotal role in the memory process) were studied. There were no age-related changes in the inhibition of Forskolin-stimulated cyclic AMP formation which contrasted to the well documented decline in acetylcholine release during aging, suggesting that these two responses are not linked to each other. Moreover, the data from the studies indicated that PI hydrolysis mediated by brain muscarinic receptors is not sensitive to age-induced changes in brain function. In addition, such receptor function was equally sensitive to blockade by phorbol esters and tetrodotoxin in young and aged rats. However, subtle changes might occur in discrete brain areas or in individual inositol phosphate species, especially inositol 1,4,5-trisphosphate, which cannot be detected by the methods employed in the present studies. It is also interesting to note that there are no age-related changes in the muscarinic receptor plasticity upon agonist pre-exposure, suggesting that treatment of memory deficit in the elderly with cholinermimetics should be performed with caution.