Abstract

Investigations of the functional integrity of receptor-mediated signal transduction are crucial to the understanding of the biochemical cascade underlying memory deficits and neurodegenerative processes of normal and pathological aging. In order to evaluate possible alterations in intracellular transduction components in aging, we studied two groups of 24- to 25-month-old Long-Evans rats selected on the basis of their cognitive performance in the Morris maze task, the aged, cognitively impaired (AI) and cognitively unimpaired (AU) animals. Production of diacylglycerol and inositol phosphates (IPs), two intracellular metabolites generated by the hydrolysis of phosphatidylinositol, were measured in selected brain areas after stimulation by various receptor agonists (1 mM carbachol, muscarinic receptors; 100 microM trans-1-aminocyclopentane-1, 3-dicarboxylate, metabotropic-glutamatergic receptors and 100 nM endothelin-1). Diacylglycerol and IPs were measured following the respective incorporation of [3H]cytidine and [3H]inositol. Data suggest that the stimulation of the inositide cascade via these receptors is at least preserved, or potentiated in the hippocampus and cortex of AI animals. Significant increases in [3H]cytidine and [3H]inositol incorporations were seen in these regions in AI vs. AU and young animals. It remains to be established if these modifications are related directly to the cognitive abilities of the aged rat as AU rats were often comparable to young animals in regard to inositide production. However, higher levels of incorporation in the AI group could reflect modifications in membrane fluidity and possibly increases in IP turnover. Because the IP cascade regulates intracellular Ca++ homeostasis, alterations of this pathway could have complex effects on normal cellular integrity as Ca++ equilibrium must be maintained for adequate neuronal viability and functions.