7
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      The G protein biased serotonin 5-HT2A receptor agonist lisuride exerts anti-depressant drug-like activities in mice

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          There is now evidence from multiple Phase II clinical trials that psychedelic drugs can exert long-lasting anxiolytic, anti-depressant, and anti-drug abuse (nicotine and ethanol) effects in patients. Despite these benefits, the hallucinogenic actions of these drugs at the serotonin 2A receptor (5-HT2AR) limit their clinical use in diverse settings. Activation of the 5-HT2AR can stimulate both G protein and β-arrestin (βArr) -mediated signaling. Lisuride is a G protein biased agonist at the 5-HT2AR and, unlike the structurally-related lysergic acid diethylamide (LSD), the drug does not typically produce hallucinations in normal subjects at routine doses. Here, we examined behavioral responses to lisuride, in wild-type (WT), βArr1-knockout (KO), and βArr2-KO mice. In the open field, lisuride reduced locomotor and rearing activities, but produced a U-shaped function for stereotypies in both βArr lines of mice. Locomotion was decreased overall in βArr1-KOs and βArr2-KOs relative to wild-type controls. Incidences of head twitches and retrograde walking to lisuride were low in all genotypes. Grooming was decreased in βArr1 mice, but was increased then decreased in βArr2 animals with lisuride. Serotonin syndrome-associated responses were present at all lisuride doses in WTs, but they were reduced especially in βArr2-KO mice. Prepulse inhibition (PPI) was unaffected in βArr2 mice, whereas 0.5 mg/kg lisuride disrupted PPI in βArr1 animals. The 5-HT2AR antagonist MDL100907 failed to restore PPI in βArr1 mice, whereas the dopamine D2/D3 antagonist raclopride normalized PPI in WTs but not in βArr1-KOs. Clozapine, SCH23390, and GR127935 restored PPI in both βArr1 genotypes. Using vesicular monoamine transporter 2 mice, lisuride reduced immobility times in tail suspension and promoted a preference for sucrose that lasted up to 2 days. Together, it appears βArr1 and βArr2 play minor roles in lisuride’s actions on many behaviors, while this drug exerts anti-depressant drug-like responses without hallucinogenic-like activities.

          Related collections

          Most cited references103

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial

          Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. Instructions to participants and staff minimized expectancy effects. Participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes. Trial Registration ClinicalTrials.gov identifier: NCT00465595
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial

            Background: Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression. Methods: In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks. Results: Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-month follow-up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (approximately 60–80% of participants continued with clinically significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression. Conclusions: In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress. Trial Registration: ClinicalTrials.gov Identifier: NCT00957359
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study

              Psilocybin is a serotonin receptor agonist that occurs naturally in some mushroom species. Recent studies have assessed the therapeutic potential of psilocybin for various conditions, including end-of-life anxiety, obsessive-compulsive disorder, and smoking and alcohol dependence, with promising preliminary results. Here, we aimed to investigate the feasibility, safety, and efficacy of psilocybin in patients with unipolar treatment-resistant depression.
                Bookmark

                Author and article information

                Contributors
                Journal
                Front Mol Biosci
                Front Mol Biosci
                Front. Mol. Biosci.
                Frontiers in Molecular Biosciences
                Frontiers Media S.A.
                2296-889X
                10 October 2023
                2023
                : 10
                : 1233743
                Affiliations
                [1] 1 Department of Psychiatry and Behavioral Sciences , Duke University Medical Center , Durham, NC, United States
                [2] 2 Mouse Behavioral and Neuroendocrine Analysis Core Facility , Duke University Medical Center , Durham, NC, United States
                [3] 3 Department of Pharmacology , University of North Carolina at Chapel Hill School of Medicine , Chapel Hill, NC, United States
                [4] 4 Center for Integrative Chemical Biology and Drug Discovery , Division of Chemical Biology and Medicinal Chemistry , Eshelman School of Pharmacy , National Institute of Mental Health Psychoactive Drug Screening Program , University of North Carolina at Chapel Hill School of Medicine , Chapel Hill, NC, United States
                [5] 5 Departments of Cell Biology and Neurobiology , Duke University Medical Center , Durham, NC, United States
                Author notes

                Edited by: Yamina Berchiche, Dr. GPCR, United States

                Reviewed by: David Sibley, National Institutes of Health (NIH), United States

                Michael H. Baumann, National Institute on Drug Abuse (NIH), United States

                Luca Posa, Cornell University, United States

                *Correspondence: William C. Wetsel, william.wetsel@ 123456duke.edu
                Article
                1233743
                10.3389/fmolb.2023.1233743
                10603247
                37900918
                434d4e6d-9f4c-4940-838e-d98fe6da250b
                Copyright © 2023 Pogorelov, Rodriguiz, Roth and Wetsel.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 02 June 2023
                : 19 September 2023
                Funding
                Funded by: National Institute on Drug Abuse , doi 10.13039/100000026;
                Funded by: Defense Advanced Research Projects Agency , doi 10.13039/100000185;
                The work was supported by NIDA grant R37-DA045657 and DARPA [Grant DARPA-5822 (HR00112020029)]. The views, opinions, and/or findings contained in this manuscript are those of the authors and should not be interpreted as representing official views, policies, or endorsement of the Department of Defense or the U.S. Government.
                Categories
                Molecular Biosciences
                Original Research
                Custom metadata
                Cellular Biochemistry

                lisuride, β-arrestin,serotonin 2a receptor,mice,prepulse inhibition,head twitch,serotonin-syndrome

                Comments

                Comment on this article