Rapid anti-PTSD-like activity of the TSPO agonist YL-IPA08: Emphasis on brain GABA, neurosteroids and HPA axis function.

Abstract

There is a serious need for fast-acting drugs to treat post-traumatic stress disorder (PTSD). Our previous studies revealed that YL-IPA08, a novel small-molecule TSPO agonist, exerted significant anti-PTSD effects in various animal models. However, the onset time of YL-IPA08 and its underlying mechanisms remain unclear. In the present study, we first investigated the time course of YL-IPA08 compared to selective serotonin reuptake inhibitors (SSRIs) in the well-known time-dependent sensitization model of PTSD. YL-IPA08 required only 2-4 days of treatment to take effect in behavioural models of PTSD, whereas sertraline required 7-8 days. Furthermore, the mechanism study revealed that YL-IPA08 elicited anti-PTSD-like effects associated with increased GABA levels and allopregnanolone efflux in the hippocampus and prefrontal cortex and increased corticosterone levels in the serum after only 5 days of treatment, whereas sertraline required 9 days. Our results demonstrate that YL-IPA08 can exert fast-onset anti-PTSD-like effects, and its mechanisms may be related to the increased GABA levels, allopregnanolone efflux and the hypothalamic-pituitary-adrenal (HPA) axis function.

• Authors: Chao Shang, Ying Guo, Jun-Qi Yao, Xin-Xin Fang, Li-Jun Sun, Xiang-Yun Jiang, Zhen-Chun Ding, Yu-Hua Ran, Heng-Lin Wang, Li-Ming Zhang, Yun-Feng Li
• Journal: Behavioural brain research (Behav Brain Res) Vol. 379 Pg. 112320 (02 03 2020) ISSN: 1872-7549 [Electronic] Netherlands
• PMID: 31669345 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019. Published by Elsevier B.V.

Chemical References

• Carrier Proteins
• Imidazoles
• N-ethyl-N-(2-pyridinylmethyl)-2-(3,4-chlorophenyl)-7-methylimidazo(1,2-a)pyridine-3-acetamide
• Pyridines
• Receptors, GABA-A
• Serotonin Uptake Inhibitors
• Tspo protein, rat
• gamma-Aminobutyric Acid
• Pregnanolone
• Sertraline
• Corticosterone

Topics

• Animals
• Behavior, Animal (drug effects)
• Carrier Proteins (agonists)
• Corticosterone (blood)
• Disease Models, Animal
• Hippocampus (drug effects, metabolism)
• Hypothalamo-Hypophyseal System (drug effects, metabolism)
• Imidazoles (pharmacokinetics, pharmacology)
• Male
• Prefrontal Cortex (drug effects, metabolism)
• Pregnanolone (metabolism)
• Pyridines (pharmacokinetics, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, GABA-A
• Selective Serotonin Reuptake Inhibitors (pharmacokinetics, pharmacology)
• Sertraline (pharmacology)
• Stress Disorders, Post-Traumatic (drug therapy)
• gamma-Aminobutyric Acid (drug effects, metabolism)