Protein synthesis inhibitor effects on neurotransmitters and memory

描述（由申请人提供）：蛋白质合成抑制剂损害新记忆的形成，阻断记忆的类似物，如长期增强和抑郁，并阻断神经变化的其他实例，包括药物耐受性和消退。这些发现为以下观点提供了基础，即记忆和大脑中其他持久的变化是由依赖于从头蛋白质合成的过程形成的。然而，由蛋白质合成抑制剂引起的健忘症可能是由蛋白质合成抑制的后果介导的，而不是记忆形成所需的新蛋白质的丧失。利用体内微透析结合局部脑注射，我们最近发现，在向杏仁核注射蛋白质合成抑制剂大霉素后，神经递质释放发生了非凡的变化。注射部位的去甲肾上腺素、多巴胺和血清素的释放在最初飙升，然后在随后的几个小时内降至远低于基线值。此外，通过联合用药阻断注射大霉素后神经递质释放的后果或逆转随后抑郁释放的后果，可以减轻大霉素引起的健忘症。这些发现表明，神经递质对药物的反应，而不是蛋白质合成本身，可能解释了异霉素引起的记忆损伤。因此，这些结果对许多关于记忆分子基础的理论的一些基本支持提出了重要的问题。本研究将通过以下方法验证最近研究结果的普遍性：(1)研究杏仁核内注射环己亚胺对生物胺释放的影响，环己亚胺抑制蛋白质合成的机制与大霉素不同；(2)研究直接给药海马的蛋白质合成抑制剂对生物胺释放的影响。这些实验的结果将扩展最近用一种抑制剂（大霉素）和一个大脑区域（杏仁核）获得的发现，以确定蛋白质合成抑制是否通过改变神经递质作用而更普遍地损害记忆。这些发现可能将蛋白质合成抑制剂对记忆的影响机制置于单胺和其他神经递质调节记忆的背景下。当代记忆和神经可塑性模型的一个核心原则是，潜在的大脑变化经历两个主要阶段，早期的蛋白质合成独立阶段和后期的蛋白质合成依赖阶段。这些观点已经成为记忆形成的分子基础的基本和很少被质疑的性质。这些观点也被应用于广泛的其他形式大脑变化的潜在机制，包括药物滥用和复发、癫痫、运动皮层和其他大脑区域在发育和中风后重组期间的组织。在这些情况下，基本证据是蛋白质合成抑制剂通过阻断需要蛋白质合成的变化机制来阻断持久的神经变化，如记忆、药物复发、癫痫或运动皮层组织。我们最近的研究结果对最常用的蛋白质合成抑制剂——大霉素获得的数据的解释提出了质疑，提供了明确的证据，表明对记忆的影响是由神经递质对蛋白质合成抑制的反应介导的。这里提出的研究考察了这些发现的普遍性的关键特性，跨越大脑区域和干扰蛋白质合成的药物。如果这些发现确实具有普遍性，就需要重新考虑多种形式的神经可塑性背后的基本分子机制，并将这些发现直接应用于记忆、发育、药物滥用、癫痫等大脑和认知功能的神经过程。

DESCRIPTION (provided by applicant): Protein synthesis inhibitors impair the formation of new memories, block analogs of memory such as long-term potentiation and depression, and block other instances of neural change including drug tolerance and extinction. These findings provide the foundation for the view that memory and other durable changes in the brain are formed by processes dependent on de novo protein synthesis. However, amnesias produced by protein synthesis inhibitors may be mediated by consequences of inhibition of protein synthesis other than loss of new proteins needed for memory formation. Using in vivo microdialysis in combination with local brain injections, we recently obtained findings showing extraordinary changes in neurotransmitter release after injections of the protein synthesis inhibitor, anisomycin, into the amygdala. Release of norepinephrine, dopamine and serotonin at the site of injection soared initially before falling well below baseline values during the subsequent hours. In addition, anisomycin-induced amnesia was attenuated by co-administration of drugs aimed at blocking the consequences of neurotransmitter release soon after anisomycin injection or at reversing the consequences of later depressed release. These findings suggest that neurotransmitter responses to the drug, rather than protein synthesis per se, may account for anisomycin-induced impairments in memory. The results thereby raise significant questions about some of the fundamental support for many theories about the molecular bases of memory. This proposal will test the generality of the recent findings by: (1) examining the effects on release of biogenic amines of intra- amygdala injections of cycloheximide, which inhibits protein synthesis by a mechanism different that of anisomycin, and (2) examining the effects on release of biogenic amines of protein synthesis inhibitors administered directly to the hippocampus. The results of these experiments will extend the recent findings obtained with one inhibitor (anisomycin) and one brain region (amygdala) to determine whether protein synthesis inhibition more generally impairs memory by altering neurotransmitter actions. These findings may place the mechanisms underlying the effects of protein synthesis inhibitors on memory within the context of modulation of memory by monoamines and other neurotransmitters. A central tenet of contemporary models of memory and neural plasticity is that the underlying brain changes pass through two major phases, an early protein synthesis- independent phase and a later protein synthesis-dependent phase. These views have become fundamental and rarely questioned properties of the molecular basis of memory formation. These views have also been applied to the mechanisms underlying a wide range of other forms of brain changes, including drug abuse and relapse, epilepsy, and organization of motor cortex and other brain areas during development and during reorganization after stroke. In each of these contexts, the basic evidence is that protein synthesis inhibitors block enduring neural changes - i.e. memory, drug relapse, epilepsy, or motor cortex organization - by blocking mechanisms of change that require protein synthesis. Our recent findings call into question the interpretation of data obtained with the most commonly used protein synthesis inhibitor, anisomycin, by provided clear evidence that the effects on memory are mediated by neurotransmitter responses to the insult of protein synthesis inhibition. The research proposed here examines key properties regarding the generality of these findings, across brain areas and across drugs that interfere with protein synthesis. If these findings are indeed general, will require a reconsideration of basic molecular mechanisms underlying many forms of neural plasticity, with direct applications of the findings to neural processes of memory, development, drug abuse, and epilepsy among other functions in brain and cognition.