Unexpected short- and long-term effects of chronic adolescent HU-210 exposure on emotional behavior

Farinha-Ferreira, M.; Rei, N.; Fonseca-Gomes, J.; Miranda-Lourenco, C.; Serrão, P.; Vaz, S. H.; Gomes, J. I.; Martins, V.; de Alves Pereira, B.; Sebastiao, A. M.

doi:10.1101/2021.12.13.472275

bioRxiv · 10.1101/2021.12.13.472275

Unexpected short- and long-term effects of chronic adolescent HU-210 exposure on emotional behavior

Farinha-Ferreira, M.·Rei, N.·Fonseca-Gomes, J.·Miranda-Lourenco, C.·Serrão, P.·Vaz, S. H.·Gomes, J. I.·Martins, V.·de Alves Pereira, B.·Sebastiao, A. M.

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Abstract

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 {Delta}9-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.

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Farinha-Ferreira, M., Rei, N., Fonseca-Gomes, J., Miranda-Lourenco, C., Serrão, P., Vaz, S. H., Gomes, J. I., Martins, V., de Alves Pereira, B., Sebastiao, A. M.. 2021-12-14. Unexpected short- and long-term effects of chronic adolescent HU-210 exposure on emotional behavior. https://doi.org/10.1101/2021.12.13.472275

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