Rapid antidepressant-like effect of non-hallucinogenic psychedelic analog lisuride, but not hallucinogenic psychedelic DOI, in lipopolysaccharide-treated mice
Youge Qu, Lijia Chang, Li Ma, Xiayun Wan, Kenji Hashimoto
Pharmacology Biochemistry and Behavior December 5, 2022 DOI: 10.1016/j.pbb.2022.173500 via OpenAlex
Summary
AI-generated from the abstractIn mice treated with lipopolysaccharide (LPS) to induce depression-like behavior, both lisuride (a non-hallucinogenic psychedelic analog) and (R)-ketamine (a novel antidepressant) reduced immobility in the forced swimming test and prevented loss of dendritic spine density in the prelimbic region of the medial prefrontal cortex, CA3, and dentate gyrus of the hippocampus. DOI, a hallucinogenic psychedelic with potent 5-HT2AR agonism, did not improve these measures. The findings suggest that the antidepressant-like effect of lisuride is not linked to 5-HT2AR-related psychedelic effects, and that 5-HT2AR may not play a major role in rapid antidepressant actions of psychedelics.
Study at a glance
| Characteristics | Controlled animal study Peer reviewed |
|---|---|
| Population | Lipopolysaccharide (LPS)-treated mice |
| Interventions | DOI lisuride (R)-ketamine |
| Dose | DOI 2.0 mg/kg, lisuride 1.0 mg/kg, (R)-ketamine 10 mg/kg |
| Duration | 23 hours after LPS administration |
| Topics | Ketamine Serotonin |
| Keywords | Lisuride Hallucinogen Pharmacology Antidepressant |
| Citations | 42 |
| Key finding | Lisuride and (R)-ketamine, but not DOI, ameliorated depression-like behavior and decreased dendritic spine density in LPS-treated mice, suggesting 5-HT2AR may not be central to rapid antidepressant actions of psychedelics. |
Abstract
Classical psychedelics with 5-hydroxytryptamine-2A receptor (5-HT2AR) agonism have rapid antidepressant actions in patients with depression. However, there is an ongoing debate over the role of 5-HT2AR in the antidepressant-like actions of psychedelics. In this study, we compared the effects of DOI (2,5-dimethoxy-4-iodoamphetamine: a hallucinogenic psychedelic drug with potent 5-HT2AR agonism), lisuride (non-hallucinogenic psychedelic analog with 5-HT2AR and 5-HT1AR agonisms), and the novel antidepressant (R)-ketamine on depression-like behavior and the decreased dendritic spine density in the brain of lipopolysaccharide (LPS)-treated mice. Saline (10 ml/kg), DOI (2.0 mg/kg), lisuride (1.0 mg/kg), or (R)-ketamine (10 mg/kg) was administered intraperitoneally to LPS (0.5 mg/kg, 23 h before)-treated mice. Both lisuride and (R)-ketamine significantly ameliorated the increased immobility time of forced swimming test, and the decreased dendritic spine density in the prelimbic region of medial prefrontal cortex, CA3 and dentate gyrus of hippocampus of LPS-treated mice. In contrast, DOI did not improve these changes produced after LPS administration. This study suggests that antidepressant-like effect of lisuride in LPS-treated mice is not associated with 5-HT2AR-related psychedelic effects. It is, therefore, unlikely that 5-HT2AR may play a major role in rapid-acting antidepressant actions of psychedelics although further detailed study is needed.