ANTISENSE OLIGODEOXYNUCLEOTIDE: GAD67 MRNA NMDA ANTAGONIST MK801 EFFECTS ON LHRH

目的观察NMDA受体拮抗剂MK 801对大鼠海马神经元的影响， 反义GAD 67诱导LHRH增加。 此前，我们已经展示了 GABA抑制的减少导致青春期增加 LHRH的释放，因此青春期的开始 但有一个 抑制性GABA张力的降低可能增加 刺激性谷氨酸张力的相对强度。 事实上， 输注GAD 67 mRNA反义寡脱氧核苷酸（oligo）， 干扰GAD合成，不仅刺激LHRH释放， 还增加了青春期前猴子的谷氨酸释放。 因此，在这项研究中，我们研究了是否影响的 GAD 67 mRNA的反义寡核苷酸可以同时通过 在青春期前和青春期猴中输注MK 801。 而在 两组猴，输注GAD 67 mRNA的反义寡核苷酸 在15 M时，单独进入S-ME刺激LHRH释放，同时 输注MK 801（5 - 5 M）和反义寡核苷酸未导致 LHRH释放量增加。 单独输注MK 801不会引起任何 效果显著。 这些结果表明，输注MK 801 阻断GAD 67 mRNA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。 数据进一步 解释为意味着使用反义寡核苷酸增加LHRH释放， GAD 67 mRNA的寡核苷酸可能部分是由于谷氨酸的增加， NMDA受体介导的张力，以及GAD的减少 合成并随后减少GABA释放。 未来方向 我们将进一步研究下降之间的因果关系 GABA和谷氨酸的增加。 关键词γ-氨基丁酸， 谷氨酸，NMDA受体，反义DNA，青春期 & RR00167

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