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Less may be more: potential procognitive and antidepressant effects of sub-hallucinogenic psilocybin doses in an animal model of depression
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Of adenosine and the blues: the adenosinergic system in the pathophysiology and treatment of major depressive disorder
Publication . Gomes, Joana I.; Farinha Ferreira, Jorge Miguel; Rei, Nádia; Gonçalves-Ribeiro, Joana; Ribeiro, Joaquim A.; Sebastião, Ana M; Vaz, Sandra H.
Major depressive disorder (MDD) is the foremost cause of global disability, being responsible for enormous personal, societal, and economical costs. Importantly, existing pharmacological treatments for MDD are partially or totally ineffective in a large segment of patients. As such, the search for novel antidepressant drug targets, anchored on a clear understanding of the etiological and pathophysiological mechanisms underpinning MDD, becomes of the utmost importance. The adenosinergic system, a highly conserved neuromodulatory system, appears as a promising novel target, given both its regulatory actions over many MDD-affected systems and processes. With this goal in mind, we herein review the evidence concerning the role of adenosine as a potential player in pathophysiology and treatment of MDD, combining data from both human and animal studies. Altogether, evidence supports the assertions that the adenosinergic system is altered in both MDD patients and animal models, and that drugs targeting this system have considerable potential as putative antidepressants. Furthermore, evidence also suggests that modifications in adenosine signaling may have a key role in the effects of several pharmacological and non-pharmacological antidepressant treatments with demonstrated efficacy, such as electroconvulsive shock, sleep deprivation, and deep brain stimulation. Lastly, it becomes clear from the available literature that there is yet much to study regarding the role of the adenosinergic system in the pathophysiology and treatment of MDD, and we suggest several avenues of research that are likely to prove fruitful.
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.
Unexpected short- and long-term effects of chronic adolescent HU-210 exposure on emotional behavior
Publication . Farinha Ferreira, Jorge Miguel; Rei, Nádia; Fonseca-Gomes, João; Miranda-Lourenço, Catarina; Serrão, Paula; Vaz, Sandra H.; Gomes, Joana I.; Martins, Valéria; Pereira, Beatriz de Alves; Sebastião, Ana M
Chronic adolescent cannabinoid receptor agonist exposure has been shown to lead to persistent increases in depressive-like behaviors. This has been a key obstacle to the development of cannabinoid-based therapeutics. However, most of the published work has been performed with only three compounds, namely Δ9-tetrahydrocannabinol, CP55,940 and WIN55,212-2. Hypothesizing that different compounds may lead to distinct outcomes, we herein used the highly potent CB1R/CB2R full agonist HU-210, and first aimed at replicating cannabinoid-induced long-lasting effects, by exposing adolescent female Sprague-Dawley rats to increasing doses of HU-210, for 11 days and testing them at adulthood, after a 30-day drug washout. Surprisingly, HU-210 did not significantly impact adult anxious- or depressive-like behaviors. We then tested whether chronic adolescent HU-210 treatment resulted in short-term (24h) alterations in depressive-like behavior. Remarkably, HU-210 treatment simultaneously induced marked antidepressant- and prodepressant-like responses, in the modified forced swim (mFST) and sucrose preference tests (SPT), respectively. Hypothesizing that mFST results were a misleading artifact of HU-210-induced behavioral hyperreactivity to stress, we assessed plasmatic noradrenaline and corticosterone levels, under basal conditions and following an acute swim-stress episode. Notably, we found that while HU-210 did not alter basal noradrenaline or corticosterone levels, it greatly augmented the stress-induced increase in both. Our results show that, contrary to previously studied cannabinoid receptor agonists, HU-210 does not induce persisting depressive-like alterations, despite inducing marked short-term increases in stress-induced reactivity. By showing that not all cannabinoid receptor agonists may induce long-term negative effects, these results hold significant relevance for the development of cannabinoid-based therapeutics.
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.
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SFRH/BD/147505/2019