背景:多巴胺在运动控制等几种生理功能中起着关键作用,学习和记忆,动机和奖励。最近报道了非典型多巴胺转运蛋白抑制剂CE-158可促进老年大鼠的行为灵活性并恢复学习和记忆。
方法:成年雄性大鼠腹腔注射CE-1581或10天,剂量为1或10mg/kg,并通过脑内微透析和同一大脑区域的单个单位细胞记录来测试内侧前额叶皮质(mPFC)中的细胞外多巴胺。此外,急性和慢性CE-158对探索行为的影响,运动活动,前脉冲抑制(PPI),还研究了工作记忆和行为灵活性。
结果:通过脑内微透析评估,CE-158剂量依赖性地增强mPFC中的多巴胺神经传递。此外,重复暴露于1mg/kg的CE-158足以增加活性锥体神经元的数量及其在同一大脑区域的放电频率。此外,10mg/kg剂量的CE-158在急性或慢性治疗后刺激相同程度的探索行为。值得注意的是,两种剂量的慢性治疗均未引起任何暗示滥用潜力的行为改变(例如,运动行为敏化)或类似精神病的影响,例如通过PPI和Y迷宫测量的感觉运动门控中断或工作记忆和行为灵活性受损。
结论:总而言之,这些发现证实了CE-158是一种有前景的认知前药物,并有助于评估其在慢性给药方案中的临床前安全性,以进行进一步的转化测试.
BACKGROUND: Dopamine plays a key role in several physiological functions such as motor control, learning and memory, and motivation and reward. The atypical dopamine transporter inhibitor S,S stereoisomer of 5-(((S)-((S)-(3-bromophenyl)(phenyl)methyl)sulfinyl)methyl)thiazole (CE-158) has been recently reported to promote behavioral flexibility and restore learning and memory in aged rats.
METHODS: Adult male rats were i.p. administered for 1 or 10 days with CE-158 at the dose of 1 or 10 mg/kg and tested for extracellular dopamine in the medial prefrontal cortex by means of intracerebral microdialysis and single unit cell recording in the same brain area. Moreover, the effects of acute and chronic CE-158 on exploratory behavior, locomotor activity, prepulse inhibition, working memory, and behavioral flexibility were also investigated.
RESULTS: CE-158 dose-dependently potentiated dopamine neurotransmission in the medial prefrontal cortex as assessed by intracerebral microdialysis. Moreover, repeated exposure to CE-158 at 1 mg/kg was sufficient to increase the number of active pyramidal neurons and their firing frequency in the same brain area. In addition, CE-158 at the dose of 10 mg/kg stimulates exploratory behavior to the same extent after acute or chronic treatment. Noteworthy, the chronic treatment at both doses did not induce any behavioral alterations suggestive of abuse potential (e.g., motor behavioral sensitization) or pro-psychotic-like effects such as disruption of sensorimotor gating or impairments in working memory and behavioral flexibility as measured by prepulse inhibition and Y maze.
CONCLUSIONS: Altogether, these findings confirm CE-158 as a promising pro-cognitive agent and contribute to assessing its preclinical safety profile in a chronic administration regimen for further translational testing.