BEHAVIORAL EFFECTS OF TRH

该项目的总体目标是研究行为 影响，神经解剖学基板，和行动的机制， 啮齿类动物中TRH的外周和中枢给药。这个项目是 出于以下几个原因启动：1）协助临床研究 在药物难治性患者中使用TRH作为抗抑郁药物 通过研究动物的行为， 神经解剖学基础; 2）进一步研究TRH是否是一种神经解剖学基础。 内源性抗惊厥药以及是否与 停药或耐受后卡马西平的抗惊厥作用 在杏仁核点燃癫痫发作模型中;和3）确定是否 对TRH行为效应的耐受性发展; 患者表示可能会发生这种情况。如果是，拖延的方法， 试图阻止或逆转耐受性。显著 迄今为止的研究结果包括以下方面的证明：1）剂量- 腹腔注射产生的自发活动依赖性增加 （腹腔注射）TRH; 2）通过i. p. 白天的TRH，而不是在晚上; 3）减少惊吓 反应，但没有改变前脉冲抑制惊吓; 4）减少 戊巴比妥诱导的睡眠时间; 5）对重复i. p. TRH无耐受性 在注射8天后出现惊吓或活动; 6）阻断许多 甲状腺切除术对TRH的行为影响; 7）慢性T3 在甲状腺切除动物中恢复TRH作用的替代品; 8） 急性T3对可卡因诱导的多动症没有影响; 9）中度 海马内注射TRH对点燃大鼠的抗惊厥作用 在阈值和阈上强度下刺激大鼠。

The overall objectives of this project are to study the behavioral effects, neuroanatomical substrates, and the mechanisms of action of peripheral and central administration of TRH in rodents. This project was initiated for several reasons: 1) to assist the clinical investigations utilizing TRH as an antidepressant medication in drug-refractory patients by examining behaviors in animals that have known neurochemical or neuroanatomical substrates; 2) to further investigate whether TRH is an endogenous anticonvulsant and whether it is related to the loss of carbamazepine's anticonvulsant effects following time-off or tolerance in the amygdala-kindled seizure model; and 3) to determine whether tolerance develops to TRH's behavioral effects; preliminary data in patients indicate that this may occur. If so, methods for delaying, preventing, or reversing tolerance would be attempted. Significant findings to date include demonstration of the following: 1) dose- dependent increases in locomotor activity produced by intraperitoneal (i.p.) TRH; 2) a potentiation of cocaine-induced hyperactivity by i.p. TRH during the day but not at night; 3) a decrease in the startle response, but no change in pre-pulse inhibition of startle; 4) a decrease in pentobarbital-induced sleep time; 5) no tolerance to repeated i.p. TRH in startle or activity following 8 days of injection; 6) blockade of many of TRH's behavioral effects by thyroidectomy; 7) a failure of chronic T3 replacement to reinstate TRH's effects in thyroidectomized animals; 8) no effect of acute T3 on cocaine-induced hyperactivity; 9) a moderate anticonvulsant effect of TRH injected into the hippocampus in kindled rats stimulated at threshold and suprathreshold intensities.