Effects of diet-induced obesity and its treatment with exenatide on expression of muscarinic acethylcholine receptor subtypes in rat hippocampus

Abstract

Molecular cloning studies have revealed the existence of five distinct muscarinic acethylcholine receptor (mAChR) subtypes (M1 to M5), which interact, via a G protein-regulated process, with multiple effector systems. The modulation of excitatory transmission by mAChRs seems particularly relevant to learning and memory processing in the hippocampal formation, where the diversity and differential localization of the receptors are likely to account for the complex cholinergic modulation in this structure. The memory can be modified by various experimental conditions such as calorie restriction, which is known to reduce the risk of Alzheimer`s disease, attenuate neuronal degeneration and behavioral deficits, and to increase life expectancy in rodents. On the other hand, experimental studies suggest a strong association between obesity and cognitive dysfunction. However, how diet-induced obesity affect memory is not fully understood. In our laboratory, in rat hippocampus membranes by radioligand binding studies with [3H]Quinuclidinyl benzilate ([3H]QNB), no detectable change in the affinity and a decrease in the density of mAChRs was previously found in diet-induced obesity when compared with control animals. The mechanisms underlying the effects of obesity on these receptors remain to be explored. Thus, the aim of this study was to investigate the effects of diet-induced obesity and its treatment with exenatide, an antidiabetogenic and potential antiobesogenic drug derived from the venom of the Gila monster Heloderma suspectum, on expression of each mAChR subtype (M1 to M5) by specific antibodies targeted to specific peptide sequences in each of the five subtypes of mAChRs, in rat hippocampus. In addition, the effects of diet-induced obesity and its treatment with exenatide on intracellular signaling pathway (phospholipase C-mediated phosphoinositide hydrolysis) linked to activation of mAChRs on hippocampus will also be studied. This action of obesity might be a key step mediating cellular events important for learning and memory. (AU)