inositol-1-4-5-trisphosphate and Memory-Disorders

Working memory (WM) is a process of actively maintaining information in the mind for a relatively short period of time, and prefrontal cortex (PFC) has been thought to play a central role in its function. However, our understanding of underlying molecular events that translate into WM behavior remains elusive. To shed light on this issue, we have used three distinct nonhuman primate models of WM where each model represents three WM conditions: normal control, WM-deficient, and recuperated to normal from WM deficiency. Based on the hypothesis that there is a common molecular substrate for the coding of WM behavior, we have studied the relationship of these animals' performance on a WM task with their PFC levels of molecular components associated with Gq-phospholipase C and cAMP pathways, with the idea of identifying the footprints of such biomolecules. We observed that in all of the primate models WM deficiency was strongly related to the reduced concentration of IP(3) in PFC, whereas recuperation of WM-deficient animals to normal condition was associated with the normalization in IP(3) level. However, this correlation was absent or weak for cAMP, active protein kinase A, dopamine D(1) receptor, and Gq protein. In addition, WM deficiency related not only to pharmacological conditions but also to aging. Thus, it is suggested that optimal IP(3) activity is essential for normal WM function and the maintenance of intracellular IP(3)-mediated Ca(2+) level in PFC may serve as biochemical substrate for the expression of WM behavior.

Topics: Amphetamine; Animals; Antipsychotic Agents; Calcium; Calcium Signaling; Central Nervous System Stimulants; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; GTP-Binding Protein alpha Subunits, Gq-G11; Haloperidol; Inositol 1,4,5-Trisphosphate; Macaca mulatta; Memory Disorders; Memory, Short-Term; Phospholipases; Prefrontal Cortex; Receptors, Dopamine D1; Recovery of Function

Earlier we have reported the effect of arecoline thiazolidinone and morpholino arecoline derivatives as muscarinic receptor 1 agonists in Alzheimer's presenile dementia models. To elucidate further our Structure-Activity Relationship (SAR) studies on the chemistry and muscarinic receptor 1 binding efficacy, a series of novel carboxamide derivatives of 2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)morpholine molecule have been designed and synthesized as a new class of M1 receptor agonists with a low toxicity effect profile that enhances memory function in animal models of Alzheimer's presenile dementia and also modulates the APP secretion from rat brain cerebrocortical slices by activating M1 receptor in vitro. Results suggest that compound 9b having methyl group at the para position of the aryl group attached to the carboxamide of morpholino arecoline could emerge as a potent molecule having antidementia activity.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Arecoline; Cerebral Cortex; Dose-Response Relationship, Drug; Humans; Inositol 1,4,5-Trisphosphate; Male; Maze Learning; Memory Disorders; Morpholines; Muscarinic Agonists; Protein Binding; Rats; Rats, Wistar; Receptor, Muscarinic M1; Structure-Activity Relationship