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Published on: October 24, 2018
Translocator protein-mediated fast-onset antidepressant-like and memory-enhancing effects in chronically stressed
Chao Shang1, Ru-Meng Yao1, Ying Guo1
1State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, PR China.
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.
Insights
A novel antidepressant, AC-5216, shows fast-acting antidepressant and memory-enhancing effects by targeting translocator protein (TSPO). This study demonstrates TSPO
Area of Science:
- Neuroscience
- Pharmacology
- Psychiatry
Background:
- There is a critical need for antidepressants with rapid onset and cognitive-enhancing properties.
- Targeting translocator protein (TSPO) is a promising strategy for novel antidepressant development.
- Data on the onset time of TSPO ligand effects are currently lacking.
Purpose of the Study:
- To investigate the fast-onset antidepressant actions of AC-5216, a selective TSPO ligand.
- To evaluate the effects of AC-5216 in a mouse model of chronic stress.
Main Methods:
- TSPO wild-type (WT) and knockout (KO) mice were subjected to a six-week chronic unpredictable stress (CUS) paradigm.
- Mice were treated with AC-5216 and assessed for depressive-like and cognitive behaviors.
- Biochemical analyses measured corticosterone, allopregnanolone, and mTOR signaling pathway proteins.
Main Results:
- A single AC-5216 dose showed anxiolytic and antidepressant-like effects in WT mice.
- Two to four days of AC-5216 treatment produced fast-onset antidepressant-like and memory-enhancing effects in stressed WT mice.
- AC-5216 rapidly restored serum corticosterone and prefrontal cortex allopregnanolone levels, and enhanced mTOR signaling and neuronal complexity.
Conclusions:
- TSPO activation by AC-5216 mediates rapid antidepressant-like and memory-enhancing effects.
- These effects are likely achieved through swift activation of mTOR signaling and restoration of dendritic complexity in the prefrontal cortex.
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