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Concurrent stress modulates the acute and post-acute effects of psilocybin in a sex-dependent manner
Publication . Farinha Ferreira, Jorge Miguel; Miranda-Lourenço, Catarina; Galipeau, Chloé; Lenkei, Zsolt; Sebastião, Ana M
There is renewed interest in psychedelics, such as psilocybin, as therapies for multiple difficult-to-treat psychiatric disorders. Even though psychedelics can induce highly pleasant or aversive experiences, depending on multiple personal and environmental factors, there is little research into how such experiences impact post-acute mood-altering actions. Here we aimed at offsetting this gap. First, we tested whether acute psilocybin effects differed between sexes. Adult male and female C57BL/6J mice received saline or psilocybin (5 mg/kg; i.p.), and head-twitch response (HTR) frequency was quantified. Notably, while psilocybin increased HTR frequency in both sexes, the effect was greater in females. We then tested if stress exposure during acute drug effects impacted post-acute psilocybin actions. Following drug treatment, mice were returned to their homecage or restrained for 1 h. Anxiety- and depression-like behaviors were assessed starting 24 h following drug administration, using the marble burying, novelty-suppressed feeding, and splash tests. Psilocybin induced anxiolytic-, but not antidepressant-like, which were fully blocked by stress in males, but only partially so in females. Lastly, we assessed the acute stress-psilocybin interaction on plasma corticosterone levels in a separate cohort of mice, treated as above. Both stress and psilocybin independently increased corticosterone levels, without additive or interactive effects being observed for either sex. Our data reveals the role of sex and peri-acute negative experiences in the acute and post-acute actions of psilocybin. These findings underline the importance of non-pharmacological factors, such as the quality of the psychedelic experience, in the mood-altering effects of psychedelics, holding significant for both their therapeutic and recreational use.
Unmoving and uninflamed: characterizing neuroinflammatory dysfunction in the Wistar‐Kyoto rat model of depression
Publication . Farinha Ferreira, Jorge Miguel; Magalhães, Daniela M; Neuparth-Sottomayor, Mariana; Rafael, H.; Miranda-Lourenço, Catarina; Sebastião, Ana M
Reductionistic research on depressive disorders has been hampered by the limitations of animal models. Recently, it has been hypothesized that neuroinflammation is a key player in depressive disorders. The Wistar-Kyoto (WKY) rat is an often-used animal model of depression, but no information so far exists on its neuroinflammatory profile. As such, we compared male young adult WKY rats to Wistar (WS) controls, with regard to both behavioral performance and brain levels of key neuroinflammatory markers. We first assessed anxiety- and depression-like behaviors in a battery consisting of the Elevated Plus Maze (EPM), the Novelty Suppressed Feeding (NSFT), Open Field (OFT), Social Interaction (SIT), Forced Swim (FST), Sucrose Preference (SPT), and Splash tests (ST). We found that WKY rats displayed increased NSFT feeding latency, decreased OFT center zone permanence, decreased EPM open arm permanence, decreased SIT interaction time, and increased immobility in the FST. However, WKY rats also evidenced marked hypolocomotion, which is likely to confound performance in such tests. Interestingly, WKY rats performed similarly, or even above, to WS levels in the SPT and ST, in which altered locomotion is not a significant confound. In a separate cohort, we assessed prefrontal cortex (PFC), hippocampus and amygdala levels of markers of astrocytic (GFAP, S100A10) and microglial (Iba1, CD86, Ym1) activation status, as well as of three key proinflammatory cytokines (IL-1β, IL-6, TNF-α). There were no significant differences between strains in any of these markers, in any of the regions assessed. Overall, results highlight that behavioral data obtained with WKY rats as a model of depression must be carefully interpreted, considering the marked locomotor activity deficits displayed. Furthermore, our data suggest that, despite WKY rats replicating many depression-associated neurobiological alterations, as shown by others, this is not the case for neuroinflammation-related alterations, thus representing a novel limitation of this model.
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Fundação para a Ciência e a Tecnologia
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Concurso de Projetos IC&DT em Todos os Domínios Científicos
Número da atribuição
PTDC/MED-FAR/4834/2021