Neuropharmacology

Biography

Biography: Takashi Kitajima

Abstract

The translocator protein 18kDa, TSPO is mainly located in the outer mitochondrial membrane of steroid producing cells, including glial cells, and regulates cholesterol transport from intracellular sources into mitochondria, a rate-limiting step in steroidogenesis. Neurosteroids act as allosteric modulators of excitatory and/or inhibitory neurotransmission and its levels are drastically changed by stress. ONO-2952, a novel selective TSPO antagonist inhibited both stress-induced increase in neurosteroid production and noradrenaline release in the brain of stressed rats. ONO-2952 dose-dependently inhibited stress-induced rectal hyperalgesia and defecation with brain TSPO occupancy of more than 50%. In addition, ONO-2952 inhibited conditioned fear stress-induced freezing behavior and cholecystokinin tetrapeptide, CCK-4 induced anxiety behavior with an efficacy equivalent to that of benzodiazepines. It should be noted that ONO-2952, unlike diazepam, did not affect passive avoidance behavior. Furthermore, ONO-2952 inhibited hyperemotionality and anxiogenic-like behavior in olfactory bulbectomized rat. In fibromyalgia models, ONO-2952 inhibited hyperalgesia induced by repeated cold stress or acid saline injection. The present findings indicate that ONO-2952 is a promising candidate for the treatment of stress-related disorders, such as irritable bowel syndrome, depression, anxiety disorders and fibromyalgia.