The Role of Hippocampal NMDA Receptors in Long-Term Emotional Responses following Muscarinic Receptor Activation

• Published in: PloS one Vol. 11; no. 1; p. e0147293
• Main Authors: Hoeller, Alexandre A, Costa, Ana Paula R, Bicca, Maíra A, Matheus, Filipe C, Lach, Gilliard, Spiga, Francesca, Lightman, Stafford L, Walz, Roger, Collingridge, Graham L, Bortolotto, Zuner A, de Lima, Thereza C M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.01.2016; Public Library of Science (PLoS)
• Subjects: Acetylcholine receptors (muscarinic); Activation; Alzheimer's disease; Animals; Anxiety; Anxiety - chemically induced; Anxiety - pathology; Behavior; Behavior, Animal - drug effects; Biology and Life Sciences; Blotting, Western; Cholinergic agents; Cholinergic transmission; Competition; Corticosterone; Dopamine; Emotions; Emotions - drug effects; Emotions - physiology; Endocrinology; Experiments; Glutamic acid receptors (ionotropic); Health sciences; Hippocampus; Hippocampus (Brain); Hippocampus - metabolism; Hippocampus - pathology; Hospitals; Hypothalamic-pituitary-adrenal axis; Inhibition (psychology); Laboratories; Male; Maze Learning - drug effects; Medicine and Health Sciences; Memantine; N-Methyl-D-aspartic acid receptors; Neurosciences; Neurotoxicity; Pharmacology; Physiology; Pilocarpine; Pilocarpine - pharmacology; Rats; Rats, Wistar; Receptor mechanisms; Receptors; Receptors, Muscarinic - chemistry; Receptors, Muscarinic - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Research and Analysis Methods; Rodents; Social Sciences; Synaptic Transmission - drug effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0147293

Extensive evidence indicates the influence of the cholinergic system on emotional processing. Previous findings provided new insights into the underlying mechanisms of long-term anxiety, showing that rats injected with a single systemic dose of pilocarpine--a muscarinic receptor (mAChR) agonist--displayed persistent anxiogenic-like responses when evaluated in different behavioral tests and time-points (24 h up to 3 months later). Herein, we investigated whether the pilocarpine-induced long-term anxiogenesis modulates the HPA axis function and the putative involvement of NMDA receptors (NMDARs) following mAChRs activation. Accordingly, adult male Wistar rats presented anxiogenic-like behavior in the elevated plus-maze (EPM) after 24 h or 1 month of pilocarpine injection (150 mg/kg, i.p.). In these animals, mAChR activation disrupted HPA axis function inducing a long-term increase of corticosterone release associated with a reduced expression of hippocampal GRs, as well as consistently decreased NMDAR subunits expression. Furthermore, in another group of rats injected with memantine--an NMDARs antagonist (4 mg/kg, i.p.)--prior to pilocarpine, we found inhibition of anxiogenic-like behaviors in the EPM but no further alterations in the pilocarpine-induced NMDARs downregulation. Our data provide evidence that behavioral anxiogenesis induced by mAChR activation effectively yields short- and long-term alterations in hippocampal NMDARs expression associated with impairment of hippocampal inhibitory regulation of HPA axis activity. This is a novel mechanism associated with anxiety-like responses in rats, which comprise a putative target to future translational studies.