Du Congwu, Yu Mei, Volkow Nora D, Koretsky Alan P, Fowler Joanna S, Benveniste Helene
Medical Department, Brookhaven National Laboratory, Upton, New York 11973-5000, USA.
J Neurosci. 2006 Nov 8;26(45):11522-31. doi: 10.1523/JNEUROSCI.3612-06.2006.
Cocaine abuse increases the risk of life-threatening neurological complications such as strokes and seizures. Although the vasoconstricting properties of cocaine underlie its cerebrovascular effects, the mechanisms underlying its neurotoxicity remain incompletely understood. Here, we use optical techniques to measure cerebral blood volume, hemoglobin oxygenation (S(t)O(2)), and intracellular calcium (Ca(2+)) to test the hypothesis that cocaine increases Ca(2+) in the brain. The effects of cocaine were compared with those of methylphenidate, which has similar catecholaminergic effects as cocaine (except for serotonin increases) but no local anesthetic properties, and of lidocaine, which has similar local anesthetic effects as cocaine but is devoid of catecholaminergic actions. To control for the hemodynamic effects of cocaine, we assessed the effects of cocaine in animals in which normal blood pressure was maintained by infusion of phenylephrine, and we also measured the effects of transient hypotension (mimicking that induced by cocaine). We show that cocaine induced significant increases ( approximately 10-15%) in Ca(2+) that were independent of its hemodynamic effects and of the anesthetic used (isofluorance or alpha-chloralose). Lidocaine but not methylphenidate also induced significant Ca(2+) increases ( approximately 10-13%). This indicates that cocaine at a dose within the range used by drug users significantly increases the Ca(2+) in the brain and its local anesthetic, but neither its catecholaminergic nor its hemodynamic actions, underlies this effect. Cocaine-induced Ca(2+) increases are likely to accentuate the neurotoxic effects from cocaine-induced vasoconstriction and to facilitate the occurrence of seizures from the catecholaminergic effects of cocaine. These findings support the use of calcium channel blockers as a strategy to minimize the neurotoxic effects of cocaine.
可卡因滥用会增加危及生命的神经并发症风险，如中风和癫痫发作。尽管可卡因的血管收缩特性是其脑血管效应的基础，但其神经毒性的潜在机制仍未完全明了。在此，我们运用光学技术测量脑血容量、血红蛋白氧合（S(t)O(2)）以及细胞内钙浓度（Ca(2+)），以检验可卡因会增加脑内Ca(2+)这一假设。将可卡因的作用与哌甲酯（其具有与可卡因相似的儿茶酚胺能效应（除了血清素增加）但无局部麻醉特性）以及利多卡因（其具有与可卡因相似的局部麻醉作用但无儿茶酚胺能作用）的作用进行比较。为控制可卡因的血流动力学效应，我们评估了在通过输注去氧肾上腺素维持正常血压的动物体内可卡因的作用，并且我们还测量了短暂性低血压（模拟可卡因诱导的低血压）的效应。我们发现，可卡因会使Ca(2+)显著增加（约10 - 15%），这与其血流动力学效应以及所用麻醉剂（异氟烷或α - 氯醛糖）无关。利多卡因而非哌甲酯也会使Ca(2+)显著增加（约10 - 13%）。这表明，吸毒者使用剂量范围内的可卡因会显著增加脑内Ca(2+)，且其局部麻醉作用而非儿茶酚胺能作用或血流动力学作用是造成这一效应的原因。可卡因诱导的Ca(2+)增加可能会加剧可卡因诱导的血管收缩所产生的神经毒性效应，并促使因可卡因的儿茶酚胺能效应而引发癫痫发作。这些发现支持使用钙通道阻滞剂作为一种策略来尽量减少可卡因的神经毒性效应。
