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bioRxiv · 10.64898/2026.04.20.719483

Distinct Modulatory Effects on Affective Biases by Different Serotonergic Psychedelics and MDMA in Male Rats: Possible Implications for Antidepressant Effects

Hinchcliffe, J.·Bartlett, J.·Thomas, C.·Golden, C.·Bortolotto, Z.·Gilmour, G.·Robinson, E.
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Abstract

Affective biases are important neuropsychological mechanisms by which emotions modulate cognition, behaviour and the subjective experience of mood. Previous studies have shown that the rapid-acting antidepressant, ketamine, and serotonergic psychedelic, psilocybin, modulate affective biases in a translational rat model. Both treatments differ from conventional, delayed onset antidepressants in being able to attenuate negatively biased memories and facilitate re-learning with a more positive affective valence. Psilocybin, but not ketamine, also positively biased new experiences, an effect similar to conventional antidepressants. This study used the different affective bias test protocols, in adult male rats, to investigate the effects of acute treatment with the serotonergic psychedelics N,N-DMT, LSD and 5-MeO-DMT, and MDMA. These drugs have different pharmacology in relation to their effects on serotonin receptor subtypes and we hypothesised this may influence their modulation of affective biases. When comparing the ability to attenuate a negatively biased memory, only MDMA had specific effects although for all drugs tested, retrieval of the FG7142-induced negative affective bias was more variable and less robust statistically. LSD attenuated the negative bias at higher doses but had non-specific effects on memory retrieval. At 24hrs post treatment only N,N-DMT had a sustained effect and none of the treatments facilitated re-learning with a more positive affective valence. However, like psilocybin and conventional antidepressants, N,N-DMT positively biased new experiences. These findings suggest there are divergent affective bias modulating effects associated with different psychedelics which may be relevant to their antidepressant effects.

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Hinchcliffe, J., Bartlett, J., Thomas, C., Golden, C., Bortolotto, Z., Gilmour, G., Robinson, E.. 2026-04-22. Distinct Modulatory Effects on Affective Biases by Different Serotonergic Psychedelics and MDMA in Male Rats: Possible Implications for Antidepressant Effects. https://doi.org/10.64898/2026.04.20.719483

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