LSD restores avoidance learning in a rat model of depression
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Introduction
Depression has been linked to dysregulation of serotonergic signalling, particularly an imbalance between 5-HT1A and 5-HT2A receptor function. While classical antidepressants gradually shift this balance, psychedelics such as LSD directly engage these receptors and may induce similar adaptations under repeated exposure. Here, we asked whether repeated LSD administration produces antidepressant-like effects in a model sensitive to subchronic, but not acute, treatment. Methods We used the olfactory bulbectomy model in rats, which reliably induces deficits in active avoidance learning and responds selectively to repeated antidepressant treatment. LSD was administered subchronically, and behavioural performance was assessed using a pole-jumping avoidance paradigm. In parallel, receptor signalling was quantified in hippocampus and frontal cortex using radioligand binding and [³⁵S]-GTPγS assays to resolve changes in 5-HT1A/2 and related monoaminergic pathways. Results Bulbectomised rats showed pronounced impairments in avoidance learning, which were largely normalised by repeated LSD treatment, while sham-operated animals did not benefit. At the neurochemical level, bulbectomy induced multiple alterations in monoaminergic signalling, of which LSD selectively restored hippocampal 5-HT2 related signalling, without broadly normalising other receptor systems. Discussion Repeated LSD produces antidepressant-like effects in a model requiring subchronic intervention, consistent with its capacity to reshape serotonergic signalling rather than acutely alter behaviour. The selective normalisation of hippocampal 5-HT2 function suggests a targeted rebalancing of receptor dynamics rather than a global monoaminergic effect. These findings support the view that psychedelics may act on mood-relevant cognitive processes via receptor-level adaptations, aligning mechanistically with core principles of antidepressant action while remaining distinct in their pharmacological profile. Notably, this work was initiated prior to the modern wave of clinical psychedelic research, anticipating later clinical work in humans. Media & dissemination: JOP | WPF 2008 | Psypost | ICPR 2020 Institution: Laboratory for Behavioural Pharmacology, Institute for Pharmacology and Toxicology, Otto-von-Guericke University Magdeburg (Germany) How to cite: Buchborn T (2026). LSD restores avoidance learning in an animal model of depression. psyborn.com/lsd-avoidance-learning.
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