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。 在动物中， 促甲状腺激素释放激素（TRH）已被证明可以抵消 酒精的副作用，矛盾的是， 反冲突效果。 在人类中，TRH可以缓解紧张和焦虑， 现在有证据表明，它可以抵消一些 乙醇的影响。 主要基于TRH的药理学特征，我们测试了 假设TRH类似物具有高中枢和低内分泌 效力（TA-0910）将降低酒精偏好（P） 大鼠 我们发现，一次腹膜内（ip）注射TA-0910，剂量- 依赖性地减少酒精（并增加水）摄入量， 并没有减少习惯酒精的P大鼠的食物或热量摄入。 促甲状腺激素或T4没有产生这些作用，表明缺乏促甲状腺激素。 内分泌受累 这些发现表明，大脑TRH系统 在大鼠酒精偏好中的作用，并暗示TRH系统的参与 该项目的具体目标是： 1)为了进一步表征TA-0910对酒精偏好的影响， P大鼠。 我们将确定：a）单一ip诱导的影响， 不同剂量TA-0910对酒精偏好的影响1、2、4、6、8、12、16、20和24 hrs.稍后; B）重复注射TA-0910的影响 （给药将基于急性效应的特征）; c）如果 对TA-0910的耐受性发展了持续时间; d）TA-0910是否会 减少酒精戒断症状;和e）如果TA-0910可以影响酒精 酒精初治大鼠的偏好和酒精消耗-p和酒精 在酒精戒断的P大鼠的偏好。 2)为了确定TA-0910降低 P大鼠的酒精偏好。 我们将确定TA-0910对 酒精偏好通过预先给予不同剂量而改变 选择性多巴胺（DA）或5-羟色胺（5-HT）拮抗剂，ip或 进入大脑的特定部位 3)确定TA-0910减少酒精的神经解剖部位 P大鼠的偏好。 我们将注射不同剂量的TA-0910（1-100 ng/部位）进入五个不同的大脑部位，以确定 减少酒精偏好。 TA-0910可降低酒精含量的研究中心 优选包括脑桥核、内侧隔和杏仁核。 网站 被认为不参与偏好（小脑，海马）将 也被测试。 4)目的：比较非偏爱（NP）大鼠和非偏爱（NP）大鼠脑TRH系统的差异。 我们将 确定是否：a）脑TRH免疫反应性水平和B）脑TRH受体 P和NP大鼠急、慢性给药前后的结合力不同 接触酒精。 另一个实验室的初步数据显示 大脑TRH水平的区域差异和大脑中可能存在的差异 P和NP大鼠之间的TRH受体亲和力。 这些目标的实现将提供科学依据， 判断TA-0910和其他TRH类似物的潜力， 减少酒精消耗和减少对酒精的渴望的特性 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.