Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy.
Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Vienna, Austria.
Int J Neuropsychopharmacol. 2023 Nov 24;26(11):784-795. doi: 10.1093/ijnp/pyad056.
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.
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.
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.
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.
多巴胺在多种生理功能中发挥着关键作用，例如运动控制、学习和记忆、动机和奖励。最近有报道称，非典型多巴胺转运体抑制剂 S,S 立体异构体 5-(((S)-((S)-(3-溴苯基)(苯基)甲基)亚砜基)甲基)噻唑（CE-158）可促进行为灵活性，并恢复老年大鼠的学习和记忆。
成年雄性大鼠连续 1 天或 10 天腹腔注射 CE-158，剂量为 1 或 10mg/kg，并通过脑内微透析和同一脑区的单细胞记录来检测内侧前额叶皮质中的细胞外多巴胺。此外，还研究了 CE-158 对探索行为、运动活动、前脉冲抑制、工作记忆和行为灵活性的急性和慢性影响。
CE-158 以剂量依赖性方式增强内侧前额叶皮质中的多巴胺神经传递，通过脑内微透析评估。此外，重复暴露于 1mg/kg 的 CE-158 足以增加同一脑区中活跃的锥体神经元的数量及其放电频率。此外，CE-158 在 10mg/kg 的剂量下，无论是急性还是慢性治疗后，都能同等程度地刺激探索行为。值得注意的是，两种剂量的慢性治疗均不会引起任何行为改变，提示滥用潜力（例如，运动行为敏感化）或类精神病样效应，如感觉运动门控中断或工作记忆和行为灵活性受损，如前脉冲抑制和 Y 迷宫测量。
总的来说，这些发现证实了 CE-158 是一种有前途的促认知药物，并有助于评估其在慢性给药方案中的临床前安全性概况，以进行进一步的转化测试。
