COCAINE ACUTELY INHIBITS DNA-SYNTHESIS IN DEVELOPING RAT-BRAIN REGIONS - EVIDENCE FOR DIRECT ACTIONS
COCAINE ACUTELY INHIBITS DNA-SYNTHESIS IN DEVELOPING RAT-BRAIN REGIONS - EVIDENCE FOR DIRECT ACTIONS
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DOI：
10.1016/0006-8993(90)90358-i
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发表时间：
1990-12-24
期刊：
影响因子：
2.9
通讯作者：
SEIDLER, FJ
中科院分区：
文献类型：
--
作者：
ANDERSONBROWN, T;SLOTKIN, TA;SEIDLER, FJ
围产期接触可卡因已被证明会导致形态和神经行为异常。在本研究中，对新生大鼠给予可卡因（30 mg/kg s.c.）在1、3、5、8、11或15日龄，在随后的30分钟内检查[H-3]胸苷掺入DNA。使用了三个大脑区域，它们的细胞成熟时间表不同：小脑，大脑皮层和中脑+脑干。可卡因抑制了所有大脑区域的DNA合成，随着动物的成熟，影响逐渐减弱;到15天大时，可卡因的影响不再显著。大分子合成的抑制对DNA具有选择性，因为可卡因对[H-3]亮氨酸掺入蛋白质的影响要小得多。虽然单次注射可卡因对[H-3]胸苷掺入的抑制作用是短暂的，但重复给药可能具有累积效应：第2、3和4天的慢性治疗不会使第5天给药的后续剂量的不良反应脱敏。此外，慢性可卡因，小脑显示出显着的反弹上升的DNA合成后24小时的最后一次剂量，一个典型的发现，在延迟细胞成熟。可卡因对发育中大脑DNA合成的抑制作用并不继发于缺血，也不继发于局部麻醉，因为用酚苄明阻断α-肾上腺素能不能提供保护，利多卡因不能代替可卡因。相反，少量（15 μ g）可卡因直接注射到中枢神经系统很容易引起DNA合成的抑制;系统给予相同剂量的可卡因没有效果。这些数据表明，可卡因损害发育中的大脑，部分是通过直接干扰DNA合成。
Perinatal exposure to cocaine has been shown to cause morphological and neurobehavioral abnormalities. In the current study, neonatal rats were given an acute injection of cocaine (30 mg/kg s.c.) at 1, 3, 5, 8, 11 or 15 days of age, and [H-3]thymidine incorporation into DNA examined over the ensuing 30 min period. Three brain regions were used that differ in their timetables of cell maturation: cerebellum, cerebral cortex and midbrain + brainstem. Cocaine inhibited DNA synthesis in all brain regions, with diminishing impact as the animals matured; by 15 days of age, the effect of cocaine was no longer significant. Inhibition of macromolecule synthesis was selective for DNA, as [H-3]leucine incorporation into protein was much less affected by cocaine. Although inhibition of [H-3]thymidine incorporation by a single injection of cocaine was short-lived, repeated administration could have cumulative effects: chronic treatment on days 2, 3 and 4 did no desensitize the adverse effect of a subsequent dose administered on day 5. Additionally, with chronic cocaine, the cerebellum displayed a pronounced rebound elevation of DNA synthesis 24 h after the last dose, a characteristic finding in delayed cell maturation. Inhibition of DNA synthesis by cocaine in developing brain was not secondary to ischemia, nor to local anesthesia, as alpha-adrenergic blockade with phenoxybenzamine afforded no protection, and lidocaine could not substitute for cocaine. In contrast, a small amount (15-mu-g) of cocaine injected directly into the central nervous system readily caused inhibition of DNA synthesis; the same dose given systematically had no effect. These data suggest that cocaine damages the developing brain, in part, through direct interference with DNA synthesis.