PULSATILE INFUSION OF GABAA RECEPTOR BLOCKER BICUCULLINE: FEMALE RHESUS PUBERTY

GABAA 受体阻断剂荷包牡丹碱的脉冲输注：雌性恒河猴青春期

• 批准号: 6312954
• 负责人: Ei Terasawa-Grilley
• 金额: $ 4.11万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1976
• 资助国家: 美国
• 起止时间: 1976-06-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6312954
• 关键词: Mammalia; clinical research; endocrine gland /system; gene therapy; growth /development; mother /infant health care; nervous system; proteins; women's health

OBJECTIVE To examine the effects of the NMDA antagonist MK801 on the antisense GAD67-induced LHRH increase. Previously, we have shown that the reduction of GABA inhibition leads to the pubertal increase in LHRH release, hence the onset of puberty. However, there is a possibility that the reduction of inhibitory GABA tone may increase the relative strength of stimulatory glutamate tone. In fact, infusion of an antisense oligodeoxynucleotide (oligo) for GAD67 mRNA, which interferes with GAD synthesis, not only stimulated LHRH release, but also increased glutamate release in prepubertal monkeys. Therefore, in this study we examined whether the effects of the antisense oligo for GAD67 mRNA could be altered by simultaneous infusion of MK801 in both prepubertal and pubertal monkeys. While in both groups of monkeys, infusion of the antisense oligo for GAD67 mRNA at 1 5M into the S-ME alone stimulated LHRH release, simultaneous infusion of MK801 at 5 5M and the antisense oligo did not result in elevated LHRH release. Infusion of MK801 alone did not cause any significant effects. These results indica te that infusion of MK801 blocks the LHRH release induced by the antisense oligo for GAD67 mRNA in both prepubertal and pubertal monkeys. The data are further interpreted to mean that the increased LHRH release with the antisense oligo for GAD67 mRNA may be partly due to an increase in glutamate tone mediated by NMDA receptors, as well as to the decrease in GAD synthesis and subsequent decrease in GABA release. FUTURE DIRECTIONS We will examine the further causal relationship between the decrease in GABA and the increase in glutamate in puberty. KEY WORDS GABA, glutamate, NMDA receptors, antisense DNA, puberty FUNDING NIH HD11355 & RR00167

目的观察N-甲基-D-天冬氨酸(NMDA)拮抗剂MK801对血管内皮细胞生长的影响。 反义GAD67诱导LHRH升高。之前，我们已经展示了 GABA抑制的减少导致青春期的增加 在LHRH的释放，因此青春期的开始。然而，有一个 抑制性GABA音调降低的可能性可能增加 刺激性谷氨酸的相对强度。事实上, 为GAD67基因注入反义寡核苷酸(OGO)， 这会干扰GAD的合成，不仅刺激LHRH的释放， 但也增加了青春期前猴子体内谷氨酸的释放。 因此，在这项研究中，我们检查了 GAD67反义寡核苷酸可同时改变 MK801在青春期前和青春期猴子体内的输注。当在 两组猴均注射GAD67反义寡核苷酸 在入舱1.5米时，S-ME单独刺激LHRH释放，同时 在5.5米处输注MK801和反义寡核苷酸均未引起 LHRH释放增加。单独输注MK801不会引起任何 效果显著。这些结果表明，MK801的输注 阻断GAD67反义寡核苷酸诱导的LHRH释放 在青春期前和青春期的猴子身上。这些数据还包括 解释为反义LHRH释放增加 GAD67基因的寡核苷酸可能部分是由于谷氨酸的增加 N-甲基-D-天冬氨酸受体介导的音调及GAD的降低 合成和随后的GABA释放减少。未来方向 我们将研究这种下降之间的进一步因果关系。 在青春期GABA和谷氨酸的增加。关键词：GABA， 谷氨酸，NMDA受体，反义DNA，青春期资助NIH HD11355 &RR00167