Involvement of allopregnanolone in the anti-PTSD-like effects of AC-5216.

Abstract

Cholesterol import into mitochondria through the translocator protein (18 KDa) (TSPO) is the starting point and an important rate-limiting step in neurosteroidogenesis. For this reason TSPO has received increased attention in the pathophysiology of post-traumatic stress disorder (PTSD). In an effort to explore the role of TSPO in mediating the anti-PTSD effect, we first assessed the effects of the TSPO ligand AC-5216 in alleviating the enhanced anxiety and fear response in a time-dependent sensitization (TDS) procedure, a rat PTSD animal model. In the present study, we showed that chronic treatment with AC-5216 caused significant suppression of the enhanced anxiety and contextual fear induced in post-TDS rats; these effects were blocked by PK11195. Furthermore, AC-5216 treatment increased the levels of allopregnanolone in the serum, prefrontal cortex, and hippocampus of post-TDS rats, and these effects were antagonized by PK11195. These results demonstrate that AC-5216 has a clear anti-PTSD-like effect, which might be partially mediated by binding to TSPO and the subsequent synthesis of allopregnanolone.

• Authors: Li-Ming Zhang, Zhi-Kun Qiu, Xiao-Fei Chen, Nan Zhao, Hong-Xia Chen, Rui- Xue, You-Zhi Zhang, Ri-Fang Yang, Yun-Feng Li
• Journal: Journal of psychopharmacology (Oxford, England) (J Psychopharmacol) Vol. 30 Issue 5 Pg. 474-81 (05 2016) ISSN: 1461-7285 [Electronic] United States
• PMID: 26783231 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2016.

Chemical References

• Anti-Anxiety Agents
• Isoquinolines
• N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide
• Purines
• Pregnanolone
• PK 11195

Topics

• Animals
• Anti-Anxiety Agents (pharmacology)
• Anxiety (drug therapy)
• Disease Models, Animal
• Fear (drug effects)
• Hippocampus (drug effects)
• Isoquinolines (pharmacology)
• Male
• Motor Activity (drug effects)
• Prefrontal Cortex (drug effects)
• Pregnanolone (pharmacology)
• Purines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Stress Disorders, Post-Traumatic (drug therapy)