INTERACTION OF ALCOHOL AND THE HPT AXIS

酒精偏好的神经生物学是复杂的，可能涉及 几个神经化学系统。在动物体内，多肽神经调节剂 促甲状腺激素释放激素(TRH)已被证明可以中和 乙醇的抑制作用，以及矛盾的是，它增强了它的 反冲突效果。在人类中，TRH可以缓解紧张和焦虑，并且 现在有证据表明，它可以抵消一些镇静剂 乙醇的影响。 主要基于TRH的药理学特征，我们测试了 假设一种TRH类似物具有高中枢和低内分泌 效价(TA-0910)会降低酒精偏好(P 老鼠。我们发现，一次腹腔注射TA-0910，剂量- 依赖减少酒精摄入量(和相应增加的水摄入量)，但 没有减少习惯饮酒的P大鼠的食物或卡路里摄入量。 这些效应不是由促甲状腺激素或T4产生的，这表明缺乏 内分泌参与。这些发现表明，大脑TRH系统具有 在大鼠酒精偏好中的作用并暗示TRH系统的参与 在男性中滥用酒精。该项目的具体目标是： 1)进一步研究TA-0910对小鼠酒精偏好的影响 P组大鼠。我们将确定：a)单一IP诱导的影响 不同剂量TA-0910对酒精偏爱1、2、4、6、8、12、16、20和24的影响 小时。之后；b)重复注射TA-0910的效果 (将根据急性影响的情况进行管理)；c)如果 对TA-0910的耐受性取决于它的耐受性；d)TA-0910是否 减少酒精戒断症状；以及e)TA-0910是否会影响酒精 饮酒幼稚大鼠的偏好和饮酒量与饮酒 酒精戒断大鼠的偏爱。 2)确定TA-0910减少的神经化学机制 P级大鼠的酒精偏好。我们将确定TA-0910对 事先服用不同剂量的酒会改变人的饮酒偏好 选择性多巴胺(DA)或5-羟色胺(5-HT)拮抗剂，ip或 进入特定的大脑部位 3)确定TA-0910减少酒精的神经解剖部位 在P大鼠中的偏爱。我们将注射不同剂量的TA-0910(1-100 NG/Site)进入五个不同的大脑区域，以确定模拟 减少饮酒偏好。TA-0910可降低酒精含量的站点 偏爱包括伏隔核、内侧隔核和杏仁核。场址 被认为不参与偏好(小脑、海马体)的人会 也要接受测试。 4)比较非偏爱(NP)大鼠和非偏爱(NP)大鼠的脑内TRH系统。我们会 确定：a)脑TRH免疫反应水平和b)脑TRH受体 P和NP大鼠急性和慢性前后结合的不同 暴露在酒精中。另一个实验室的初步数据显示 脑内TRH水平的地区差异及可能的脑内差异 P和NP大鼠的TRH受体亲和力。 这些目标的实现将提供科学证据，以便 判断TA-0910和其他TRH类似物的潜力 减少饮酒和减少饮酒欲望的特性 在人类身上。

The neurobiology of alcohol preference is complex and likely involves several neurochemical systems. In animals, the peptide neuromodulator thyrotropin-releasing hormone (TRH) has been shown to counteract the depressant effects of ethanol and, paradoxically, to potentiate its anticonflict effects. In humans, TRH may relieve tension and anxiety, and there is now evidence suggesting it can counteract some of the depressant effects of ethanol. Based primarily on the pharmacological profile of TRH, we tested the hypothesis that a TRH analog with reported high central and low endocrine potency (TA-0910) would reduce alcohol preference in alcohol preferring (P) rats. We showed that one intraperitoneal (ip) injection of TA-0910, dose- dependently reduced alcohol (and commensurately increased water) intake but did not reduce food or caloric intake in P rats accustomed to alcohol. These effects were not produced by thyrotropin or T4 indicating a lack of endocrine involvement. These findings suggest that brain TRH systems have a role in alcohol preference in rats and imply involvement of TRH systems in alcohol abuse in man. The specific aims of this project are: 1) To further characterize the effects of TA-0910 on alcohol preference in P rats. We will determine: a) the effects of single ip inductions of different doses of TA-0910 on alcohol preference 1,2,4,6,8,12,16,20 and 24 hrs. later; b) the effects of repeated injections of TA-0910 (administration will be based on profiles of acute effects); c) if tolerance to TA-0910 develops an how long it lasts; d) whether TA-0910 will reduce alcohol withdrawal symptoms; and e) if TA-0910 can affect alcohol preference and alcohol consumption in alcohol naive-p rats and alcohol preference in alcohol-withdrawn P rats. 2) To determine the neurochemical mechanisms by which TA-0910 reduces alcohol preference in P rats. We will determine if effects of TA-0910 on alcohol preference are altered by prior administration of different doses of selective dopamine (DA) or serotonin (5-HT) antagonists, injected ip or into specific brain sites 3) To determine the neuroanatomical sites where TA-0910 reduces alcohol preference in P rats. We will inject different doses of TA-0910 (1-100 ng/site) into five different brain sites to determine where the analog reduces alcohol preference. Sites where TA-0910 may act to reduce alcohol preference include nucleus accumbens, medial septum, and amygdala. Sites thought not to be involved in preference (cerebellum, hippocampus) will also be tested. 4) To compare brain TRH systems in and non-preferring (NP) rats. We will determine if: a) brain TRH immunoreactive levels and b) brain TRH receptor binding are different in P and NP rats before and after acute and chronic exposure to alcohol. Preliminary data from another laboratory indicate regional differences in brain TRH levels and possible differences in brain TRH receptor affinity between P and NP rats. Achievement of these aims will provide scientific evidence upon which to judge the potential of TA-0910 and other TRH analogs with similar properties to attenuate alcohol consumption and reduce craving for alcohol in humans.