Toner C C, Stamford J A
Anaesthetics Unit (Neurotransmission Laboratory), St Bartholomew's and the Royal London School of Medicine and Dentistry, Royal London Hospital, U.K.
Neuroscience. 1997 Dec;81(4):999-1007. doi: 10.1016/s0306-4522(97)00259-5.
Massive striatal dopamine release during cerebral ischaemia has been implicated in the resulting neuronal damage. Sodium influx is an early event in the biochemical cascade during ischaemia and blockade of sodium channels may increase resistance to ischaemia by reducing energy demand involved in compensation for sodium and potassium fluxes. In this study, we have determined the effects of opening and blockade of voltage-gated sodium channels on hypoxia/hypoglycaemia-induced dopamine release. Slices of rat caudate nucleus were maintained in a slice chamber superfused by an oxygenated artificial cerebrospinal fluid containing 4 mM glucose. Ischaemia (hypoxia/hypoglycaemia) was mimicked by a switch to a deoxygenated artificial cerebrospinal fluid containing 2 mM glucose and dopamine release was measured using fast cyclic voltammetry. In drug-free (control) slices, there was a 2-3 min delay after the onset of hypoxia/hypoglycaemia followed by a rapid dopamine release event which was associated with anoxic depolarization. In slices treated with the Na+ channel opener, veratridine (1 microM), the time to onset of dopamine release was shortened (101 +/- 20 s, compared with 171 +/- 8 s in controls, P < 0.05). Conversely, phenytoin (100 microM), lignocaine (200 microM) and the highly selective sodium channel blocker, tetrodotoxin (1 microM) markedly delayed and slowed dopamine release vs paired controls. In the majority of cases, dopamine release was biphasic after sodium channel blockade: a slow phase preceded a more rapid dopamine release event. The latter was associated with anoxic depolarization. Neither the fast nor the slow release events were affected by pretreatment with the selective dopamine uptake blocker GBR 12935 (0.2 microM), suggesting that uptake carrier reversal did not contribute to these events. In conclusion, sodium channel antagonism delays and slows hypoxia/hypoglycaemia-induced dopamine release in vitro. Furthermore, sodium channel blockade delays anoxic depolarization and its associated neurotransmitter release, revealing an earlier dopamine release event that does not result from reversal of the uptake carrier.
脑缺血期间纹状体大量多巴胺释放与随后的神经元损伤有关。钠内流是缺血生化级联反应中的早期事件，阻断钠通道可通过减少钠钾离子流补偿所需的能量需求来增加对缺血的耐受性。在本研究中，我们确定了电压门控钠通道开放和阻断对缺氧/低血糖诱导的多巴胺释放的影响。将大鼠尾状核切片置于充满含4 mM葡萄糖的含氧人工脑脊液的切片槽中。通过切换到含2 mM葡萄糖的脱氧人工脑脊液来模拟缺血（缺氧/低血糖），并使用快速循环伏安法测量多巴胺释放。在无药物（对照）切片中，缺氧/低血糖发作后有2 - 3分钟的延迟，随后是快速的多巴胺释放事件，这与缺氧去极化有关。在用钠通道开放剂藜芦定（1 microM）处理的切片中，多巴胺释放开始的时间缩短（101±20秒，而对照组为171±8秒，P<0.05）。相反，苯妥英（100 microM）、利多卡因（200 microM）和高选择性钠通道阻滞剂河豚毒素（1 microM）与配对对照组相比，显著延迟并减缓了多巴胺释放。在大多数情况下，钠通道阻断后多巴胺释放是双相的：一个缓慢阶段先于一个更快的多巴胺释放事件。后者与缺氧去极化有关。快速和缓慢释放事件均不受选择性多巴胺摄取阻滞剂GBR 12935（0.2 microM）预处理的影响，这表明摄取载体逆转对这些事件没有作用。总之，钠通道拮抗作用在体外延迟并减缓了缺氧/低血糖诱导的多巴胺释放。此外，钠通道阻断延迟了缺氧去极化及其相关的神经递质释放，揭示了一个并非由摄取载体逆转引起的更早的多巴胺释放事件。
