The role of hippocampal NMDA receptors in long-term emotional responses following muscarinic receptor activation

Alexandre A. Hoeller, Ana Paula R Costa, Maira A. Bicca, Filipe C. Matheus, Gilliard Lach, Francesca Spiga, Stafford L. Lightman, Roger Walz, Graham L. Collingridge, Zuner A. Bortolotto, Thereza C M De Lima

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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.
Original languageEnglish
Article numbere0147293
Number of pages18
JournalPLoS ONE
Issue number1
Publication statusPublished - 21 Jan 2016


  • Anxiety
  • HPA axis
  • Muscarinic receptors
  • Pilocarpine
  • NMDA receptors
  • Memantine


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