Synaptic Plasticity in the BNST and Drug Dependence

BNST 中的突触可塑性和药物依赖性

• 批准号: 6968408
• 负责人: WALTER G FRANCESCONI
• 金额: $ 23.24万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6968408
• 关键词: NMDA receptors; behavioral /social science research tag; cocaine; drug /alcohol abstinence; drug addiction; drug withdrawal; ethanol; heroin; laboratory rat; long term potentiation; neural plasticity; thalamus

DESCRIPTION (provided by applicant): The bed nucleus of the stria terminalis (BNST) is a crucial component of the extended amygdala circuitry that has been implicated in the long-lasting dysregulations of the brain stress and reward systems that are induced by drugs of abuse and are believed to play a motivational role in continued drug use. The lateral subdivision of the BNST, which receives ample innervation from the amygdala, is involved in stress responses and in the long-lasting motivational dysregulation associated with drug dependence. High frequency stimulation (HFS) of the area of the stria terminalis in brain slices induces a strong N-Methyl-D-Aspartate (NMDA)-type glutamate receptors-dependent long term potentiation (LTP) of field potential in the dorso-lateral BNST. Rats with a history of ethanol dependence did not show LTP in the dorso-lateral BNST during protracted withdrawal despite normal basal synaptic responses. We have observed that the induction of LTP in the dorso-lateral BNST was impaired during protracted abstinence in alcohol self-administering rats with a history of alcohol dependence and in cocaine self-administering rats with a history of escalated cocaine intake. A less pronounced impairment in the capacity for LTP induction was seen in rats that with a history of stable (non-escalated) self-administration of alcohol or cocaine. These observations of a common dysregulation during protracted abstinence from either alcohol or cocaine intake suggests that synaptic plasticity in the lateral BNST may be key to regulating drug intake in post-dependent individuals. We now propose to extend these studies to define the time-dependence of this phenomenon and to determine whether the same dysregulation of synaptic plasticity can also be demonstrated in the lateral BNST of opiate-dependent rats. The present exploratory proposal from a new investigator will lay the foundations for the systematic investigation of the role of BNST synaptic plasticity in the maladaptive neurobiological events that are believed to be behind the development of compulsive drug intake and vulnerability to relapse.

描述（由申请人提供）：Stria末端（BNST）的床核是扩展的杏仁核电路的关键组成部分，它与滥用药物引起的脑压力和奖励系统的长期失调有关，并被认为在继续使用药物中发挥了激励作用。 BNST的横向细分从杏仁核中获得了充足的神经支配，参与了压力反应以及与药物依赖性相关的持久动机失调。脑切片中质末端的高频刺激（HFS）诱导强大的N-甲基-D-天冬氨酸（NMDA） - 型谷氨酸受体依赖性的长期增强（LTP）的型型甲植物的型号的野外BNST。尽管基础突触反应正常，但具有乙醇依赖性病史的大鼠在延长的戒断期间并未显示LTP。我们已经观察到，在酒精自我管理的大鼠中持续节制，具有酒精依赖史和可卡因自我管理的大鼠，具有升级可卡因摄入量的史上，在dorso-siptral BNST中的LTP诱导受到了损害。在大鼠中看到了稳定的（非估算）酒精或可卡因的自我给药病史的大鼠，在LTP诱导的能力上造成了不太明显的损害。这些观察到与酒精或可卡因摄入的持续节制期间常见失调的观察结果表明，BNST的突触可塑性可能是调节后依赖性个体中药物摄入的关键。现在，我们建议扩展这些研究，以定义这种现象的时间依赖性，并确定是否还可以在鸦片依赖性大鼠的侧面BNST中证明突触可塑性的相同失调。本新研究者的目前探索性提议将奠定基础，以系统地研究BNST突触可塑性在疾病的神经生物学事件中的作用，这些事件被认为是强迫性药物摄入量和复发脆弱性的发展。