Translocator protein–mediated fast-onset antidepressant-like and memory-enhancing effects in chronically stressed mice
| Autor: | Chao Shang, Yun-Feng Li, Jian-Min Zhang, Li-Ming Zhang, Zhen-Chun Ding, You-Zhi Zhang, Rui Xue, Ying Guo, Ru-Meng Yao, Yu-Hua Ran, Huai-Shan Wang, Li-Jun Sun |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Prefrontal Cortex
Pregnanolone Pharmacology Antidepressant like Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Receptors GABA Memory Translocator protein Animals Medicine Pharmacology (medical) 030304 developmental biology Mice Knockout 0303 health sciences Behavior Animal biology business.industry Pyramidal Cells TOR Serine-Threonine Kinases Allopregnanolone Recognition Psychology Dendrites Fast onset Antidepressive Agents Mice Inbred C57BL Psychiatry and Mental health Anti-Anxiety Agents chemistry Purines Chronic Disease biology.protein Corticosterone business Stress Psychological 030217 neurology & neurosurgery |
| Zdroj: | Journal of Psychopharmacology. 34:441-451 |
| ISSN: | 1461-7285 0269-8811 |
| DOI: | 10.1177/0269881119896304 |
| Popis: | Background: Fast-acting and cognitive-enhancing antidepressants are desperately needed. Activation of translocator protein (18 kDa, TSPO) is a novel strategy for developing potential antidepressants, but there are no data available on the onset time of TSPO ligands. This study aimed to investigate the fast-onset antidepressant actions of AC-5216, a selective TSPO ligand, in TSPO knock-out (KO) mice. Methods: TSPO wild-type (WT) and KO mice were subjected to a six-week chronic unpredicted stress (CUS) paradigm. Then, the mice were treated with AC-5216 and tested with depressive and cognitive behaviours. Results: A single dose of AC-5216 (0.3 mg/kg) exerted anxiolytic- and antidepressant-like actions in TSPO WT mice. Moreover, in chronically stressed WT mice, two to four days of AC-5216 treatment (0.3 mg/kg, once per day) produced fast-onset antidepressant-like effects in the novelty-suppressed feeding and sucrose preference tests, as well as memory-enhancing effects in the novel object recognition test. In addition, a rapid (with five days of treatment) restoration of serum corticosterone levels and prefrontal cortex (PFC) allopregnanolone levels was found. Further studies showed that in these stress-exposed WT mice, AC-5216 significantly increased the levels of mTOR signalling-related proteins (mBDNF, p-mTOR, PSD-95, synapsin-1, GluR1), as well as the total dendritic length and branching points of pyramidal neurons in the PFC. Conclusions: These results suggest that TSPO mediates the fast-onset antidepressant-like and memory-enhancing effects of AC-5216, possibly through the rapid activation of mTOR signalling and restoration of dendritic complexity in the PFC. |
| Databáze: | OpenAIRE |
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