Department of Pediatrics, Div. of Neurology, University of Cincinnati College of Medicine and Cincinnati Children's Research Foundation, Cincinnati, OH, 45229, USA.
Psychopharmacology (Berl). 2019 Jul;236(7):2243-2258. doi: 10.1007/s00213-019-05221-3. Epub 2019 Mar 27.
Methamphetamine (MA) is an abused psychostimulant that causes cognitive deficits after chronic use. Neostriatal dopamine receptors play a role in MA monoamine neurotoxicity. Blocking dopamine receptors prior to MA exposure in adult rats attenuates monoamine reductions and reactive gliosis.
We tested whether blocking dopamine receptors protects against cognitive deficits.
First, we determined the effects of MA alone versus MA in combination with the dopamine receptor D1 antagonist SCH-23390 or the dopamine receptor D2 antagonist sulpiride on cFos expression and monoamines at the age when rats in the cognitive experiment were to begin testing and monoamines in rats after cognitive testing.
SCH-23390 infused into the neostriatum prior to systemic administration of MA attenuated MA-induced cFos activation while sulpiride induced cFos activation. Two weeks after MA, rats had dopamine and serotonin reductions that were attenuated by each antagonist. Other rats treated the same way, were tested for egocentric learning and memory in the Cincinnati water maze, for navigational strategy in a star water maze, and spatial learning and memory in a Morris water maze. Pre-treatment with SCH-23390 or sulpiride attenuated the effects of MA on egocentric and spatial learning and memory. MA-treated rats showed a shift from an egocentric to a disorganized strategy in the star maze that was less disorganized in groups receiving MA and an antagonist. Post-behavior monoamine reductions remained but were attenuated by the antagonists but not identically to what was seen in rats not behaviorally tested.
The results show for the first time that dopamine receptors are mediators of MA-induced cognitive deficits.
甲基苯丙胺（MA）是一种滥用的精神兴奋剂，长期使用会导致认知功能障碍。新纹状体多巴胺受体在 MA 单胺神经毒性中起作用。在成年大鼠暴露于 MA 之前阻断多巴胺受体可减轻单胺减少和反应性神经胶质增生。
我们测试了阻断多巴胺受体是否可以预防认知功能障碍。
首先，我们确定了 MA 单独作用以及 MA 与多巴胺受体 D1 拮抗剂 SCH-23390 或多巴胺受体 D2 拮抗剂舒必利联合作用对 cFos 表达和单胺类物质的影响，这些影响发生在进行认知实验的大鼠开始测试的年龄以及认知测试后大鼠的单胺类物质。
SCH-23390 预先注入新纹状体，然后系统给予 MA，可减轻 MA 诱导的 cFos 激活，而舒必利则诱导 cFos 激活。MA 给药后 2 周，大鼠的多巴胺和 5-羟色胺减少，这两种拮抗剂都可以减轻。以同样方式处理的其他大鼠接受了自我中心学习和记忆的辛辛那提水迷宫测试、导航策略的星形水迷宫测试以及空间学习和记忆的 Morris 水迷宫测试。SCH-23390 或舒必利的预处理减轻了 MA 对自我中心和空间学习和记忆的影响。MA 处理的大鼠在星形迷宫中从自我中心策略转变为混乱策略，而接受 MA 和拮抗剂的大鼠的策略则不那么混乱。行为后单胺类物质减少仍然存在，但被拮抗剂减轻，但与未进行行为测试的大鼠所见并不完全相同。
这些结果首次表明，多巴胺受体是 MA 诱导的认知功能障碍的介质。
