Baba Satoko, Murai Takeshi, Nakako Tomokazu, Enomoto Takeshi, Ono Michiko, Shimizu Isao, Ikeda Kazuhito
Drug Development Research Laboratories, Sumitomo Dainippon Pharma, Co., Ltd., Osaka, Japan.
Ikeda Lab., Drug Development Research Laboratories, Sumitomo Dainippon Pharma, Co., Ltd., Osaka, Japan.
Behav Brain Res. 2015;287:120-6. doi: 10.1016/j.bbr.2015.03.025. Epub 2015 Mar 21.
Previous pilot clinical studies have shown that the serotonin 5-HT1A receptor agonist tandospirone has beneficial effect on cognitive deficits associated with schizophrenia. In the present study, we evaluated the cognitive efficacy of tandospirone, given alone or in combination with the antipsychotic blonanserin, risperidone or haloperidol, on executive function in marmosets using the object retrieval with detour (ORD) task. Treatment with tandospirone alone at 20 and 40 mg/kg increased the number of correct responses in the difficult trial, while risperidone (0.3mg/kg) and haloperidol (0.3mg/kg) decreased the number of correct responses in this trial. On the other hand, blonanserin (0.1-0.3mg/kg), an atypical antipsychotic highly selective for dopamine D2/D3 and serotonin 5-HT2A receptors, did not affect the number of correct responses in both the easy and difficult trials. Co-treatment with tandospirone (20mg/kg) and risperidone (0.1-0.3mg/kg) or haloperidol (0.1-0.3mg/kg) did not improve animals' performance in the difficult trial. However, co-treatment with tandospirone and blonanserin (0.1-0.3mg/kg) increased the number of correct responses in the difficult trial. In addition, treatment with the dopamine D1 receptor agonist SKF-81297 at 1mg/kg increased marmosets correct responses in the difficult trial. These results suggest that tandospirone is a promising candidate for the treatment of cognitive deficits associated with schizophrenia and that adjunctive treatment with tandospirone and blonanserin is more appropriate for cognitive deficits than combination therapy with tandospirone and risperidone or haloperidol. The results of this study also indicate that the putative mechanism of action of tandospirone might be related to enhancement of dopamine neurotransmission via activation of the 5-HT1A receptor.
先前的试点临床研究表明，5-羟色胺5-HT1A受体激动剂坦度螺酮对与精神分裂症相关的认知缺陷具有有益作用。在本研究中，我们使用迂回取物（ORD）任务评估了单独给予坦度螺酮或与抗精神病药物布南色林、利培酮或氟哌啶醇联合使用时，坦度螺酮对狨猴执行功能的认知疗效。单独使用20和40mg/kg的坦度螺酮治疗可增加困难试验中的正确反应次数，而利培酮（0.3mg/kg）和氟哌啶醇（0.3mg/kg）则减少了该试验中的正确反应次数。另一方面，对多巴胺D2/D3和5-羟色胺5-HT2A受体具有高度选择性的非典型抗精神病药物布南色林（0.1-0.3mg/kg）在简单和困难试验中均未影响正确反应次数。坦度螺酮（20mg/kg）与利培酮（0.1-0.3mg/kg）或氟哌啶醇（0.1-0.3mg/kg）联合治疗并未改善动物在困难试验中的表现。然而，坦度螺酮与布南色林（0.1-0.3mg/kg）联合治疗增加了困难试验中的正确反应次数。此外，1mg/kg的多巴胺D1受体激动剂SKF-81297治疗增加了狨猴在困难试验中的正确反应次数。这些结果表明，坦度螺酮是治疗与精神分裂症相关认知缺陷的有前途的候选药物，并且坦度螺酮与布南色林联合治疗比坦度螺酮与利培酮或氟哌啶醇联合治疗更适合于认知缺陷。本研究结果还表明，坦度螺酮的推定作用机制可能与通过激活5-HT1A受体增强多巴胺神经传递有关。
