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，如长时程增强和抑郁，并阻断其他神经变化的实例，包括药物耐受性和消退。这些发现为以下观点提供了基础：大脑中的记忆和其他持久变化是通过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产生的健忘症可能是由蛋白质合成抑制的结果介导的，而不是记忆形成所需的新蛋白质的丢失。使用体内微透析结合局部脑注射，我们最近获得的结果显示，蛋白质合成抑制剂，茴香霉素，注射到杏仁核后，神经递质释放的显着变化。注射部位的去甲肾上腺素、多巴胺和5-羟色胺的释放在随后的几个小时内下降到远低于基线值之前最初飙升。此外，茴香霉素诱导的健忘症是衰减的共同管理的药物，旨在阻断神经递质释放的后果后不久，茴香霉素注射或逆转的后果，后来压抑的释放。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，可能是茴香霉素诱导的记忆障碍的原因。因此，这些结果对许多关于记忆分子基础的理论提出了一些重要的问题。该建议将通过以下方式检验最近发现的一般性：（1）检查杏仁核内注射放线菌酮对生物胺释放的影响，放线菌酮通过与茴香霉素不同的机制抑制蛋白质合成，和（2）检查直接给予海马体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的研究结果与一种抑制剂（茴香霉素）和一个大脑区域（杏仁核），以确定蛋白质合成抑制是否更普遍地损害记忆通过改变神经递质的行动。这些发现可能将蛋白质合成抑制剂对记忆影响的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中心原则是，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性质，很少受到质疑。这些观点也被应用于广泛的其他形式的大脑变化的机制，包括药物滥用和复发，癫痫，以及运动皮层和其他大脑区域在发育过程中的组织和中风后的重组。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-即记忆，药物复发，癫痫或运动皮层组织。我们最近的研究结果提出了问题的解释与最常用的蛋白质合成抑制剂，茴香霉素，通过提供明确的证据，对记忆的影响是由神经递质的反应介导的蛋白质合成抑制的侮辱获得的数据。这里提出的研究检查了这些发现的一般性的关键特性，跨大脑区域和跨干扰蛋白质合成的药物。如果这些发现确实是普遍的，将需要重新考虑许多形式的神经可塑性的基本分子机制，并将这些发现直接应用于记忆，发育，药物滥用和癫痫等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.