Acute Ketamine Facilitates Fear Memory Extinction in a Rat Model of PTSD Along With Restoring Glutamatergic Alterations and Dendritic Atrophy in the Prefrontal Cortex

Stress represents a major risk factor for psychiatric disorders, including post-traumatic stress disorder (PTSD). Recently, we dissected the destabilizing effects of acute stress on the excitatory glutamate system in the prefrontal cortex (PFC). Here, we assessed the effects of single subanesthetic...

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Published in:Frontiers in pharmacology 2022-03, Vol.13, p.759626-759626
Main Authors: Sala, Nathalie, Paoli, Caterina, Bonifacino, Tiziana, Mingardi, Jessica, Schiavon, Emanuele, La Via, Luca, Milanese, Marco, Tornese, Paolo, Datusalia, Ashok K, Rosa, Jessica, Facchinetti, Roberta, Frumento, Giulia, Carini, Giulia, Salerno Scarzella, Floramarida, Scuderi, Caterina, Forti, Lia, Barbon, Alessandro, Bonanno, Giambattista, Popoli, Maurizio, Musazzi, Laura
Format: Article
Language:English
Subjects:
acute stress
dendritic arborization
glutamate transmission
ketamine
Pharmacology
prefrontal cortex (PFC)
PTSD
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Summary:Stress represents a major risk factor for psychiatric disorders, including post-traumatic stress disorder (PTSD). Recently, we dissected the destabilizing effects of acute stress on the excitatory glutamate system in the prefrontal cortex (PFC). Here, we assessed the effects of single subanesthetic administration of ketamine (10 mg/kg) on glutamate transmission and dendritic arborization in the PFC of footshock (FS)-stressed rats, along with changes in depressive, anxious, and fear extinction behaviors. We found that ketamine, while inducing a mild increase of glutamate release in the PFC of naïve rats, blocked the acute stress-induced enhancement of glutamate release when administered 24 or 72 h before or 6 h after FS. Accordingly, the treatment with ketamine 6 h after FS also reduced the stress-dependent increase of spontaneous excitatory postsynaptic current (sEPSC) amplitude in prelimbic (PL)-PFC. At the same time, ketamine injection 6 h after FS was found to rescue apical dendritic retraction of pyramidal neurons induced by acute stress in PL-PFC and facilitated contextual fear extinction. These results show rapid effects of ketamine in animals subjected to acute FS, in line with previous studies suggesting a therapeutic action of the drug in PTSD models. Our data are consistent with a mechanism of ketamine involving re-establishment of synaptic homeostasis, through restoration of glutamate release, and structural remodeling of dendrites.
ISSN:1663-9812
1663-9812
DOI:10.3389/fphar.2022.759626