Behavioral characterization of mice lacking the A3 adenosine receptor:: Sensitivity to hypoxic neurodegeneration
Behavioral characterization of mice lacking the A3 adenosine receptor:: Sensitivity to hypoxic neurodegeneration
复制标题
DOI：
10.1023/a:1023601007518
复制
发表时间：
2003-06-01
影响因子：
4
通讯作者：
Jacobson, KA
中科院分区：
文献类型：
--
作者：
Fedorova, IM;Jacobson, MA;Jacobson, KA
1.利用A(3)腺苷受体(A(3)AR(-/-))功能缺失的小鼠，研究了A(3)腺苷受体(A(3)AR(-/-))在行为评估中的潜在神经保护作用，包括镇痛、运动、抑郁和焦虑的预测，以及轻度缺氧对认知和神经元存活的影响。未治疗的A(3)AR(-/-)小鼠接受标准行为模式的测试，包括在开阔场地的活动、在热板、甩尾、悬尾和游泳测试中的表现以及在高架+迷宫中的表现。此外，小鼠被反复暴露在含有一氧化碳(CO)的低氧环境中。使用情景恐惧条件反射测试来评估这种治疗的认知效果。检测后，用标准组织学和形态计量学技术测定大鼠海马区CA1、CA2和CA3区锥体神经元的密度。A(3)AR(-/-)小鼠在旷场测试、高架迷宫(手臂进入次数)和明暗箱(转换次数)中表现出更多的活动。然而，在两种不同的抗抑郁活性测试(游泳和尾部悬挂测试)中，他们花了更多的时间不动。A(3)AR(-/-)小鼠也表现出热板痛觉减少的证据，但没有甩尾试验。此外，A(3)AR(-/-)小鼠在一氧化碳(CO)诱导的缺氧发作后更容易受到海马锥体神经元的损伤。CO染毒1周后，野生型(A(3)AR(+/+))和A(3)AR(-/-)小鼠海马区锥体神经元均有中度丢失。然而，在A(3)AR(+/+)小鼠中，CA2-3亚区神经元死亡的程度不如A(3)AR(+/+)小鼠明显。这种神经元的丧失伴随着认知功能的下降，这是通过情景恐惧条件反射确定的。重复给予A(3)AR选择性拮抗剂MRS 1523(5-propyl-2-ethyl-4-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate 1 mg/kg，在野生型小鼠身上复制了这些组织学和认知变化。这些结果表明，A(3)AR功能的药物或遗传抑制增强了运动功能的某些方面，并抑制了脊髓上水平的疼痛处理，同时在预测抗抑郁作用的测试中起到了镇静剂的作用。与以前关于A(3)AR激动剂的神经保护作用的报道一致，A(3)AR(-/-)小鼠在反复缺氧时表现出神经变性的增加。
1. The potential neuroprotective actions of the A(3) adenosine receptor (A(3)AR) were investigated using mice with functional deletions of the A(3)AR (A(3)AR(-/-)) in behavioral assessments of analgesia, locomotion, tests predictive of depression and anxiety, and the effects of mild hypoxia on cognition and neuronal survival.2. Untreated A(3)AR(-/-) mice were tested in standard behavioral paradigms, including activity in the open field, performance in the hot-plate, tail-flick, tail-suspension, and swim tests, and in the elevated plus maze. In addition, mice were exposed repeatedly to a hypoxic environment containing carbon monoxide (CO). The cognitive effects of this treatment were assessed using the contextual fear conditioning test. After testing, the density of pyramidal neurons in the CA1, 2, and 3 subfields of the hippocampus was determined using standard histological and morphometric techniques.3. A(3)AR(-/-) mice showed increased locomotion in the open field test, elevated plus maze (number of arm entries) and light/dark box (number of transitions). However, they spent more time immobile in two different tests of antidepressant activity (Swim and tail suspension tests). A(3)AR(-/-) mice also showed evidence of decreased nociception in the hotplate, but not tail-flick tests. Further, A(3)AR(-/-) mice were more vulnerable to hippocampal pyramidal neuron damage following episodes of carbon monoxide (CO)-induced hypoxia. One week after exposure to CO a moderate loss of pyramidal neurons was observed in all hippocampal subfields of both wild-type (A(3)AR(+/+)) and A(3)AR(-/-) mice. However, the extent of neuronal death in the CA2-3 subfields was less pronounced in A(3)AR(+/+) than A(3)AR(+/+) mice. This neuronal loss was accompanied by a decline in cognitive function as determined using contextual fear conditioning. These histological and cognitive changes were reproduced in wild-type mice by repeatedly administering the A(3)AR-selective antagonist MRS 1523 (5-propyl-2-ethyl-4-propyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate 1 mg/kg i.p.).4. These results indicate that pharmacologic or genetic suppression of A(3)AR function enhances some aspects of motor function and suppresses pain processing at supraspinal levels, while acting as a depressant in tests predictive of antidepressant action. Consistent with previous reports of the neuroprotective actions of A(3)AR agonists, A(3)AR(-/-) mice show an increase in neurodegeneration in response to repeated episodes of hypoxia.