Persistent reversal of addiction behavior by a transient treatment

通过短暂的治疗持续逆转成瘾行为

• 批准号: 8598435
• 负责人: K. Ulrich Bayer
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598435
• 关键词: Acute; Adverse effects; Affect; Amphetamine Addiction; Amphetamines; Behavior; Behavioral; Binding; Blood - brain barrier anatomy; Brain region; Cells; Chronic; Co-Immunoprecipitations; Cocaine; Cocaine Dependence; Complex; Data; Dose; Drug Sensitization; Event; Funding; Future; Genetic; Glutamate Receptor; Hippocampus (Brain); Human; Intensive Care; Intervention; Knockout Mice; Lead; Learning; Letters; Long-Term Potentiation; Mediating; Mediator of activation protein; Memory; Mus; Mutant Strains Mice; Mutation; N-Methylaspartate; Nucleus Accumbens; Peptides; Pharmacological Treatment; Physiological; Prevention; Rattus; Retrograde amnesia; Self Administration; Short-Term Memory; Signal Transduction; Slice; Specificity; Synaptic plasticity; Testing; Therapeutic; Treatment Protocols; Virus; addiction; base; calmodulin-dependent protein kinase II; expectation; improved; in vivo; inhibitor/antagonist; interest; long term memory; memory acquisition; mutant; next generation; novel; novel therapeutic intervention; preference; public health relevance; therapy development

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.

描述（由申请人提供）：Ca 2 +/钙调蛋白依赖性蛋白激酶II（CaMKII）和NMDA型谷氨酸受体（NMDAR）亚基GluN 2B是长时程增强（LTP）的两种中枢介质，LTP是一种突触可塑性形式，被认为是生理和适应不良成瘾相关学习和记忆的基础。该提案将测试CaMK II/GluN 2 B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的初步数据成瘾行为和最近的结果与“正常”的LTP。值得注意的是，这项研究的结果将同样重要，即使他们导致 拒绝我们的假设（例如，如果我们发现抑制CaMKII活性足以逆转成瘾行为，而不需要破坏CaMKII/GluN 2B复合物）。(Aim 1）我们将在这里首先建立一种在体内破坏CaMK II/GluN 2B复合物的药物治疗。(Aim 2）然后，我们将确定这种治疗对成瘾行为逆转的影响。这将直接决定一种新的成瘾治疗方法的可行性。(Aim 3）最后，我们将确定对“正常”记忆的影响，这在临床上也很重要。对记忆获得的急性但可逆的干扰，甚至擦除最近尚未巩固的记忆，都是临床上可接受的副作用。然而，虽然已经巩固的记忆的意外擦除也将具有很高的科学影响，但需要在治疗开发中克服（例如，通过靶向特定的大脑区域，即NAc，这是可以做到的，但需要更密集的护理）。我们将在此采用高度严格的药物遗传学方法。虽然药理学治疗能够确定治疗相关性（通过实现成瘾行为的预防和逆转之间的时间区分），但两种特定的小鼠突变体将确定靶特异性：CaMKII敲除小鼠将测试CaMKII特异性，而具有不能结合CaMKII的突变体GluN 2B的小鼠将测试CaMKII/GluN 2B复合物作为特异性靶标。重要的是，这种方法还克服了突变小鼠中常见的潜在代偿作用：如果突变小鼠由于这种代偿作用仍然发展成成瘾行为（正常或稍微降低的水平），如果它们的突变确实是治疗的相关靶点，则药理学治疗在这些小鼠中应该不再有效。