Neurobehavioral effects of adolescent GHB

青少年 GHB 对神经行为的影响

• 批准号: 7032784
• 负责人: RATNA SIRCAR
• 金额: $ 24.62万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7032784
• 关键词: NMDA receptors; adolescence (12-20); age difference; anxiety; autoradiography; behavioral /social science research tag; drug abuse; gamma hydroxybutyrate; gender difference; glutamates; immunocytochemistry; laboratory rat; learning; memory; neural plasticity; neurochemistry; neuropsychological tests; neuropsychology; neurotransmitters; pharmacokinetics; psychopharmacology; substance abuse related behavior; western blottings

Gamma hydroxybutyrate (GHB) occurs naturally in the brain. Exogenously it is used recreationally for its euphoric and anabolic effects, and therapeutically in the treatment of narcolepsy and as an anesthetic agent. GHB belongs to the class of substances referred to as "club drugs", and, like them, has been reorted to be a "date rape drug". Illicit use of GHB has been associated with significant adverse effects such as amnesia, dizziness, confusion, agitation, hallucination, and at very high doses respiratory depression, unconsciousness, coma and death. Compromised cognitive function, particularly memory lapses, is a major concern with GHB use, as with all date rape drugs. Yet in animals, effect of GHB on memory has never been studied. GHB use and abuse is most prevalent among adolescents and young adults, but neurobehavioral and pharmacological effects of GHB in adolescent animals remains unknown. This is a major caveat in GHB animal literature, since adolescents are known to differ from adults in their response to other drugs of abuse. Compared to adult rats, adolescent rats have been shown to be less sensitive to the sedative and motor impairing effects of ethanol. Also, following ethanol exposure adolescent rats show greater memory impairments than adults. In a preliminary study, we have shown that GHB exposure in adolescent rats cause significant deficits in spatial learning and memory (SL&M). The present study will systematically investigate the immediate and persistent effects of adolescent GHB exposure on SL&M. Hypotheses to be tested are: (1) effects of adolescent GHB exposure on learning and memory are long-term and gender dependent, (2) behavioral effects of GHB exposure in adolescent rats differ from those in adult rats, (3) adolescent GHB exposure do not impair non-mnemonic functions such as anxiety, (4) adolescent GHB-induced deficits in SL&M are associated with alterations in neurotransmitter functions, (5) adolescent GHB-induced deficits in SL&M can be reversed by pharmacologic interventions. Male and female rats will be exposed to low doses of GHB or saline during the adolescent period and tested as adolescents, and as adults, for impairments in spatial learning and memory and anxiety. The metabolism and clearance rates of GHB in blood and brain of adolescent and adult rats are not known, and will be measured in this study to look for ontogenic differences in GHB pharmacokinetics at the two ages. We have some evidence indicating that adolescent GHB treatment is associated with altered regulation of the N-methyl-D-aspartate (NMDA) receptor. In this proposal, adolescent GHB on neuroadaptations in the glutamatergic system will be investigated. The proposed studies will be the first study where an animal model using adolescent rats will be used to explore the neurochemical and psychopharmacological effects of GHB. Data obtained from these studies will further define plasticity of the central nervous system during the adolescent period in rats. Such information will be relevant to GHB exposure in human adolescents, and help in the development of novel prevention and/or treatment strategies.

γ 羟基丁酸 (GHB) 天然存在于大脑中。外源性地，它因其欣快感和合成代谢作用而被娱乐性地使用，并且在治疗上用于治疗发作性睡病和作为麻醉剂。 GHB 属于被称为“俱乐部毒品”的物质类别，并且与它们一样，已被归为“约会强奸毒品”。非法使用 GHB 会导致严重的不良反应，例如健忘、头晕、精神错乱、烦躁、幻觉，以及高剂量时的呼吸抑制、意识不清、昏迷和死亡。与所有约会强奸药物一样，使用 GHB 会导致认知功能受损，尤其是记忆衰退。然而，在动物中，GHB 对记忆的影响从未有过。 被研究过。 GHB 使用和滥用在青少年和年轻人中最为普遍，但是 GHB 对青春期动物的神经行为和药理作用仍不清楚。这是 GHB 动物文献中的一个重要警告，因为众所周知，青少年对其他滥用药物的反应与成年人不同。与成年大鼠相比，青春期大鼠对乙醇的镇静和运动损伤作用不太敏感。此外，暴露于乙醇后，青少年大鼠比成年大鼠表现出更严重的记忆障碍。在一项初步研究中，我们发现青少年大鼠接触 GHB 会导致空间学习和记忆 (SL&M) 显着缺陷。本研究将系统地调查青少年 GHB 暴露对 SL&M 的直接和持续影响。要测试的假设是：(1) 青少年 GHB 暴露对学习和记忆的影响是长期的且取决于性别，(2) 青少年大鼠 GHB 暴露的行为影响不同于其他大鼠 在成年大鼠中，(3) 青少年 GHB 暴露不会损害焦虑等非记忆功能，(4) 青少年 GHB 诱导的 SL&M 缺陷与神经递质功能的改变相关，(5) 青少年 GHB 诱导的 SL&M 缺陷可以可以通过药物干预来逆转。雄性和雌性大鼠将在青少年时期接触低剂量的 GHB 或盐水，并在青少年和成年后进行空间学习、记忆和焦虑障碍的测试。青少年和成年大鼠血液和大脑中 GHB 的代谢和清除率尚不清楚，本研究将对其进行测量，以寻找两个年龄段 GHB 药代动力学的个体差异。我们有一些证据表明青少年 GHB 治疗与 N-甲基-D-天冬氨酸 (NMDA) 受体调节的改变有关。在本提案中，将研究青少年 GHB 对谷氨酸能系统神经适应的影响。拟议的研究将是第一项使用青春期大鼠的动物模型来探索神经化学和 GHB 的精神药理学作用。从这些研究中获得的数据将进一步确定大鼠青春期中枢神经系统的可塑性。此类信息将与人类青少年的 GHB 暴露相关，并有助于制定新的预防和/或治疗策略。