Author(s): Farinha-Ferreira, Miguel ; Rei, Nádia ; Fonseca-Gomes, João ; Miranda-Lourenço, Catarina ; Serrão, Paula ; Vaz, Sandra H. ; Gomes, Joana I. ; Martins, Valéria ; de Alves Pereira, Beatriz ; Sebastião, Ana M.
Date: 2022
Persistent ID: http://hdl.handle.net/10362/151392
Origin: Repositório Institucional da UNL
Subject(s): Adolescence; Anxiety; Cannabinoids; Depression; HU-210; Stress; Pharmacology; Cellular and Molecular Neuroscience
Funding Information: Work was supported by project funding from Fundação para a Ciência e para a Tecnologia (FCT) ( PTDC/MED-FAR/30933/2017 and PTDC/MED-FAR/4834/2021 ) and by H2020-WIDESPREAD-05-2017-Twinning (EpiEpinet) under grant agreement No. 952455 . MF-F ( SFRH/BD/147505/2019 ), NR ( PD/BD/113463/2015 ), JF-G ( PD/BD/114441/2016 ) and CM-L ( SFRH/BD/118238/2016 ) are supported by PhD fellowships from FCT . The funding sources had no involvement in study design, preparation of the manuscript, or decision regarding its submission. Publisher Copyright: © 2022
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.
