Mechanisms/GHB/models/acute/chronic GBH intoxication.

由于其兴奋和镇静作用，伽马-羟基丁酸酯偶尔或长期被人类滥用。过量服用GHB可导致严重的意识抑郁、癫痫发作、呕吐甚至死亡，而长期滥用可能与显著的戒断综合征有关。因此，摄取GHB会引起大脑的生物变化，这可能会对个人的福祉产生重大影响。这项提议的目标是描述GHB滥用的小鼠模型中大脑的特定变化。这项提议要检验的基本假设是，长期服用GHB通过GABAB受体通过GHB效应影响哺乳动物的大脑。这会导致可归因于生理过程变化的行为变化，如神经元放电和兴奋性和抑制性突触传递。由于GABAB受体可能是GHB作用的主要靶点，口服GHB的慢性效应应被GABAB受体拮抗剂抑制，或在GABAB受体已被基因消融的动物中不存在。目前，对GHB滥用引起的中枢神经系统的变化知之甚少。我们提出了一些基于口服GHB处理的小鼠的行为和电生理检查的研究。这三个具体目标中的每一个都涉及温室气体的作用机制的关键特征。其目的是1)在野生型小鼠和GABAB受体敲除小鼠中确定长期口服GHB和戒断的体内神经元相关性；2)建立长期口服GHB后小鼠大脑皮层细胞和神经元网络的变化；以及3)确定GABAB受体拮抗剂和GHB受体拮抗剂NCS-382是否对GHB诱导的行为和细胞特性的变化提供保护。为了实现这些目标，将在接受行为和电生理测试的小鼠身上进行GHB的口服治疗。此外，高分辨率的电生理记录将从IR-DIC方法识别的神经元中获得，并对记录的细胞进行解剖重建。选择性GABAB受体拮抗剂将被使用，而新产生的GABAB受体敲除动物将作为一种先进的工具来测试GABAB受体在这些过程中的参与。这项研究有望对GHB在哺乳动物大脑中诱导的变化产生新的和具体的见解。通过开发和表征GHB滥用的小鼠模型，我们的研究将打开进一步利用转基因小鼠研究GHB对大脑或其他器官的影响的可能性。了解与GHB滥用有关的具体变化将有助于更好地掌握与GHB摄取有关的临床问题，包括急性中毒、长期滥用和GHB戒断综合征。

Gamma-hydroxybutyrate is abused by humans occasionally or chronically due to its euphoric and sedative effects. An overdose of GHB can lead to a severe depression of the consciousness, seizures, vomiting and even death, while long-term abuse can be associated with a marked withdrawal syndrome. Thus, ingestion of GHB causes biological changes in the brain that may have major influence on the well-being of the individual. The goal of this proposal is to characterize specific alterations in the brain in a mouse model of GHB abuse. The fundamental hypothesis to be tested by the present proposal is that chronic GHB administration affects the mammalian brain through GHB effects via GABAB receptors. This causes behavioral alterations attributable to changes in physiological processes, such as neuronal firing and excitatory and inhibitory synaptic transmission. As GABAB receptors may be the major target of GHB action, the chronic effects of oral GHB should be dampened by GABAB receptor antagonists, or should be absent in animals where the GABAB receptor has been genetically ablated. Presently, changes in the CNS caused by GHB abuse are poorly understood. We propose a number of investigations relying on behavioral and electrophysiological examination of orally GHB-treated mice. Each of the three specific aims addresses critical features of the mechanism of action of GHB. The aims are 1) to determine the in vivo neuronal correlates of chronic, oral GHB-administration and withdrawal in wild-type mice and in GABAB receptor knockout mice; 2) to establish the cellular and neuronal network changes in the cerebral cortex in the mice after chronic, oral GHB- administration; and 3) to ascertain whether GABAB-receptor antagonists and GHB-receptor antagonist NCS-382 offer protection against the GHB-induced changes in behavior and cellular properties. To accomplish these goals, oral treatment with GHB will be carried out in mice subjected to behavioral and electrophysiological tests. Furthermore, high resolution electrophysiological recordings will be obtained from neurons identified with IR-DIC methods and anatomical reconstruction of the recorded cells. Selective GABAB receptor antagonists will be used, while the newly generated GABAB receptor knockout animals will serve as an advanced tool to test the involvement of GABAB receptors in these processes. The study is expected to yield novel and specific insights into the GHB-induced changes in the mammalian brain. By developing and characterizing a mouse model of GHB abuse, our study will open the possibility of further using genetically altered mice for studying the effects of GHB on the brain or other organs. Understanding the specific alterations that accompany GHB abuse will lead to a better grasp of the clinical problems associated with GHB ingestion, including acute intoxication, long-term abuse, and the GHB withdrawal syndrome.