Anti-stress effects of ONO-2952, a novel translocator protein 18 kDa antagonist, in rats

Neuropharmacology. 2015 Dec;99:51-66. doi: 10.1016/j.neuropharm.2015.07.011. Epub 2015 Jul 17.

Abstract

Accumulating evidence has shown the pathophysiological significance of the translocator protein 18 kDa (TSPO) in the central nervous system. In this study, we evaluated the beneficial effects of ONO-2952, a novel TSPO antagonist in rat stress models. ONO-2952 potently bound both rat and human TSPO (Ki=0.330-9.30 nmol/L) with high selectivity over other receptors, transporters, ion channels and enzymes. ONO-2952 inhibited both neurosteroid accumulation and noradrenaline release in the brain of rats exposed to acute stress. The inhibitory effect of ONO-2952 on stress-induced noradrenaline release was attenuated by co-treatment with the TSPO agonist CB34 in a dose-dependent manner. ONO-2952, at 0.3 mg/kg or higher, dose-dependently suppressed restraint stress-induced defecation in rats with brain TSPO occupancy of more than 50%. In addition, ONO-2952, at 1 mg/kg or higher, suppressed conditioned fear stress-induced freezing behavior in rats with an efficacy equivalent to that of diazepam, given orally at 3 mg/kg. Results of the passive avoidance learning test revealed that ONO-2952, unlike diazepam, did not affect learning and memory even at doses 10 times higher than its effective doses in the stress models. The present findings indicate that ONO-2952 is a promising candidate for the treatment of stress-related disorders.

Keywords: Neurosteroid; Noradrenaline; ONO-2952; Stress; Translocator protein 18 kDa.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amygdala / drug effects
  • Amygdala / metabolism
  • Animals
  • Avoidance Learning / drug effects
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Cyclopropanes / chemistry
  • Cyclopropanes / pharmacokinetics
  • Cyclopropanes / pharmacology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Freezing Reaction, Cataleptic / drug effects
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Heterocyclic Compounds, 4 or More Rings / pharmacokinetics
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Humans
  • Male
  • Psychotropic Drugs / chemistry
  • Psychotropic Drugs / pharmacokinetics
  • Psychotropic Drugs / pharmacology*
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptors, GABA / metabolism
  • Receptors, GABA-A / metabolism
  • Restraint, Physical
  • Stress, Psychological / drug therapy*
  • Stress, Psychological / metabolism

Substances

  • Carrier Proteins
  • Cyclopropanes
  • Heterocyclic Compounds, 4 or More Rings
  • ONO-2952
  • Psychotropic Drugs
  • Receptors, GABA
  • Receptors, GABA-A
  • TSPO protein, human
  • Tspo protein, rat