title: The Role of Hippocampal NMDA Receptors in Long-Term Emotional Responses following Muscarinic Receptor Activation.
abstract: 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.
authors.affiliation: Postgraduate Program in Medical Sciences, Center of Health Sciences, University Hospital, Federal University of Santa Catarina, Florianópolis, SC, 88040-970, Brazil.|Department of Pharmacology, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, SC, 88040-970, Brazil.|Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Dorothy Hodgkin Building, Bristol, BS1 3NY, United Kingdom.
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: Hoeller
authors.affiliation: Department of Pharmacology, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, SC, 88040-970, Brazil.
authors.forename: Ana Paula R
authors.initials: AP
authors.lastname: Costa
authors.affiliation: Department of Pharmacology, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, SC, 88040-970, Brazil.
authors.forename: Maíra A
authors.initials: MA
authors.lastname: Bicca
authors.affiliation: Department of Pharmacology, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, SC, 88040-970, Brazil.
authors.forename: Filipe C
authors.initials: FC
authors.lastname: Matheus
authors.affiliation: Department of Pharmacology, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, SC, 88040-970, Brazil.|Institute of Pharmacology, Innsbruck Medical University, Innsbruck, 6020, Austria.
authors.forename: Gilliard
authors.initials: G
authors.lastname: Lach
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Dorothy Hodgkin Building, Bristol, BS1 3NY, United Kingdom.
authors.forename: Francesca
authors.initials: F
authors.lastname: Spiga
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Dorothy Hodgkin Building, Bristol, BS1 3NY, United Kingdom.
authors.forename: Stafford L
authors.initials: SL
authors.lastname: Lightman
authors.affiliation: Postgraduate Program in Medical Sciences, Center of Health Sciences, University Hospital, Federal University of Santa Catarina, Florianópolis, SC, 88040-970, Brazil.|Department of Clinical Medicine, Center of Health Sciences, University Hospital, Federal University of Santa Catarina, Florianópolis, SC, 88040-970, Brazil.
authors.forename: Roger
authors.initials: R
authors.lastname: Walz
authors.affiliation: Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Dorothy Hodgkin Building, Bristol, BS1 3NY, United Kingdom.
authors.forename: Graham L
authors.initials: GL
authors.lastname: Collingridge
authors.affiliation: Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Dorothy Hodgkin Building, Bristol, BS1 3NY, United Kingdom.
authors.forename: Zuner A
authors.initials: ZA
authors.lastname: Bortolotto
authors.affiliation: Department of Pharmacology, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, SC, 88040-970, Brazil.
authors.forename: Thereza C M
authors.initials: TC
authors.lastname: de Lima
mesh_terms: D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000473:pathology*; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D004644:Emotions / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D010862:Pilocarpine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000737:chemistry / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D011976:Receptors, Muscarinic; D016194:Receptors, N-Methyl-D-Aspartate; D010862:Pilocarpine