Persistent reversal of addiction behavior by a transient treatment

描述（由申请人提供）：Ca2+/钙调素依赖性蛋白激酶II （CaMKII）和nmda型谷氨酸受体（NMDAR）亚基GluN2B是长期增强（LTP）的两个中心介质，LTP是一种突触可塑性的形式，被认为是生理和适应性不良成瘾相关学习和记忆的基础。该提案将测试CaMKII/GluN2B复合物的短暂破坏(a)持续逆转安非他明和可卡因诱导的成瘾相关行为和(b)严重干扰记忆巩固但不逆转已建立的记忆的假设。这些假设是基于最近关于成瘾行为的初步数据和“正常”LTP的最新结果。值得注意的是，这项研究的结果即使领先，也同样重要

DESCRIPTION (provided by applicant): The Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the NMDA-type glutamate receptor (NMDAR) subunit GluN2B are two central mediators of long-term potentiation (LTP), a form of synaptic plasticity thought to underlie both physiological and maladaptive addiction-related learning and memory.. The proposal will test the hypotheses that transient disruption of the CaMKII/GluN2B complex (a) persistently reverses amphetamine- and cocaine-induced addiction- related behavior and (b) acutely interferes with memory consolidation but does not reverse established memory. These hypotheses are based on recent preliminary data on addiction behavior and on recent results with "normal" LTP. Notably, the results of this study will be equally significant even if they lead to rejection of our hypotheses (for instance in case we instead find that inhibition of CaMKII activity is sufficient for reversal of addiction behavior, without requirement for disruption of th CaMKII/GluN2B complex). (Aim 1) We will here first establish a pharmacological treatment that disrupts the CaMKII/GluN2B complex in vivo. (Aim 2) Then, we will determine the effect of such treatment on reversal of addiction behavior. This will directly determine feasibility of a novel therapeutic approach to addiction. (Aim 3) Finally, we will determine the effect on "normal" memory, which is also clinically important. Acute but reversible interference with memory acquisition and even erasure of recent not yet consolidated memory would be clinically acceptable side-effects. However, while an unexpected erasure also of already consolidated memory would be of high scientific impact, it would need to be overcome in therapy development (for instance by targeting a specific brain region, i.e. the NAc, which could be done but would require more intensive care). We will here utilize a highly rigorous pharmaco-genetic approach. While the pharmacological treatment enables determining the therapeutic relevance (by enabling the temporal distinction between prevention and reversal of addiction behavior), two specific mouse mutant will determine target-specificity: a CaMKII knock-out mouse will test for CaMKII-specificity, while a mouse with mutant GluN2B incapable of CaMKII binding will test for the CaMKII/GluN2B complex as the specific target. Importantly, this approach also overcomes potential compensatory effects that are frequently seen in mutant mice: If the mutant mice still develop addiction behavior (either to normal or to somewhat reduced levels) due to such compensatory effects, the pharmacological treatment should be no longer effective in these mice, if their mutation is indeed the relevant target of the treatment.