THE EFFECTS OF COCAINE ON TYROSINE HYDROXYLASE ACTIVITY IN THE RAT BRAIN

可卡因对大鼠脑内酪氨酸羟化酶活性的影响

• 批准号: 3759485
• 负责人: J M MASSERANO
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3759485
• 关键词: brain metabolism; cocaine; dopamine; enzyme activity; frontal lobe /cortex; human tissue; hydroxylation; laboratory rat; neuropharmacology; neurotransmitter metabolism; nucleus accumbens; tegmentum; tyrosine; tyrosine 3 monooxygenase

Dopaminergic neurons in the brain are thought to play an important role in the etiology of schizophrenia. One theory of schizophrenia suggests that it is due to an imbalance of dopamine in certain brain areas. The drug cocaine enhances the action of dopamine in the brain. Humans who take cocaine in high doses for a prolonged period of time may suffer symptoms of pro longed depression and apathy similar to the negative symptoms seen in schizophrenic patients. Similarly, the repeated administration of high doses of cocaine in rats can produce a decrease in locomotor activity and a lack of 'the usual sensitization state seen with lower dose stimulant drug challenge. In earlier studies, we evaluated the effects of cocaine administration on the activity of tyrosine hydroxylase in five brain regions of rats. Cocaine, administered in a dose of 10 mg/kg intraperitoneally, given twice a day for seven days, produced a significant increase in tyrosine hydroxylase activity of approximately 50% in the ventral tegmental area at six and twelve weeks after the last cocaine administration. Similar studies have been performed measuring the in vivo hydroxylation of tyrosine in these brain regions. Cocaine produced a significant decrease in tyrosine hydroxylation in the frontal cortex (30%) and nucleus accumbens (34%) compared with saline treated rats six weeks after the last injection, with no significant differences after two week& These data suggest that cocaine increases tyrosine hydroxylase activity in the ventral tegmental area in response to decreased synthesis of dopamine in the frontal cortex and nucleus accumbens. Recently, we have initiated studies to measure tyrosine hydroxylase activity in human brain tissue. Tyrosine hydroxylase activity can be detected in human cortical tissue with the use of concentrator-filtration system (Centricon, Amicon). However, this activity is relatively low (twice blank) and additional studies are in progress to enhance the sensitivity of the assay.

大脑中的多巴胺能神经元被认为在 精神分裂症的病因。一种精神分裂症的理论认为 这是由于某些大脑区域的多巴胺失衡。的 可卡因能增强多巴胺在大脑中的作用。的人类 长期服用高剂量可卡因可能会 长期抑郁和冷漠的症状类似于阴性 精神分裂症患者的症状同样，重复 在大鼠中给予高剂量的可卡因可以产生减少 在运动活动和缺乏“通常的敏化状态看到 低剂量的兴奋剂药物挑战。在早期的研究中，我们 评估了可卡因给药对 酪氨酸羟化酶的五个大脑区域的大鼠。口服避孕药 以10 mg/kg的剂量腹膜内给药，每天两次，持续7天 天，产生了酪氨酸羟化酶活性的显着增加 在6岁和12岁时腹侧被盖区大约有50% 在最后一次可卡因注射后的几周。 类似的研究已经 进行了测量，在这些大脑中酪氨酸的体内羟基化 地区辅酶A可显著降低酪氨酸 额叶皮质（30%）和丘脑核（34%）的羟基化 与最后一次注射后6周盐水处理的大鼠相比， 两周后无显著差异&这些数据表明， 可卡因增加腹侧被盖酪氨酸羟化酶活性 额叶皮质多巴胺合成减少反应区 和神经核。最近，我们开始研究， 酪氨酸羟化酶的活性。 酪氨酸 羟化酶活性可以在人皮质组织中用 使用浓缩过滤系统（Centricon、Amicon）。 但这 活性相对较低（两倍空白），其他研究正在进行中。 提高检测灵敏度的进展。