Receptor specific mechanisms underlying psychedelic effects on affective behaviors

Abstract

AbstractBackgroundAlzheimer’s Disease (AD) patients experience affective symptoms. Conventional therapies to address affective symptoms have limited efficacy in AD, alternative options, like psychedelics, have received interest. Psychedelics work through serotonergic pathways ‐ a neuromodulatory system with dysfunction in AD ‐mechanisms underlying behavioral changes and potential efficacy of their use are unknown. Evaluation of mechanisms underlying behavioral effects is needed to determine their potential as interventions. Psychedelics act through serotonin receptors, not serotonin re‐uptake inhibition characteristic of typical antidepressants. We investigate psychedelics’ mechanism of action as a potential effector of hedonic tone to assess its potential use for affective symptoms in AD.MethodWT mice were subject to one of three paradigms: (1) a 10‐day social defeat stress (SDS); (2) an injection of 2,5‐Dimethoxy‐4‐iodoamphetamine (DOI); or (3) SDS with DOI. SDS was used instead of an AD proteinopathy model to induce effects like anhedonia. Afterwards, mice underwent behavioral tests to evaluate compulsivity and affect. An additional group will receive DOI +serotonin receptor antagonistsResultFirst, SDS increased time spent in closed arms of the elevated plus maze (EPM; p = 0.0068) indicating an increase in anxiety. It also increased nest shredding (NST; p = 0.206), indicating an increase in compulsivity.Secondly, an injection of DOI decreased time spent in closed arms (p = 0.0151) indicating decrease in anxiety, and decreased nest shredding (p = 0.0325) indicating a decrease in compulsivity.Lastly, we expect that DOI will decrease anxiety and compulsivity. We expect to find the inverse to be true in mice that receive DOI +antagonist.ConclusionWe are showing that a traumatic stressor, like that a human might experience pre‐AD, induces potentially maladaptive affective behavioral changes. Here, we’ve demonstrated that psychedelics can act to recover affective dysfunction by activation of serotonin receptors. Because of degeneration of key serotonergic nuclei in AD, the use of serotonin reuptake inhibitors has limited efficacy for addressing symptoms like depression. Psychedelics may offer improved outcomes for AD patients in this regard due to its alternative mechanism of action. Further work to evaluate the efficacy of psychedelics in animal models more closely approximating AD‐type changes in serotonergic systems will help refine this understanding and guide potential clinical applications.