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

10 Citations (Scopus)
305 Downloads (Pure)

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.
Original languageEnglish
Article numbere0147293
Number of pages18
JournalPLoS ONE
Volume11
Issue number1
DOIs
Publication statusPublished - 21 Jan 2016

Keywords

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

Fingerprint

Dive into the research topics of 'The role of hippocampal NMDA receptors in long-term emotional responses following muscarinic receptor activation'. Together they form a unique fingerprint.

Cite this