Molecular mechanisms of excessive alcohol consumption and relapse-like behavior

过量饮酒和复发样行为的分子机制

基本信息

批准号：
8335515
负责人：
Reginald DeVon Cannady
金额：
$ 2.94万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8335515
关键词：
Acids Address Alcohol consumption Alcohol dependence Alcoholism Alcohols Amino Acids Amygdaloid structure Behavior Behavioral Brain Brain region Cues Data Dependence Excitatory Synapse Glutamates Goals Heavy Drinking Immunohistochemistry Ion Channel Lead Light Maps Mediating Molecular Neurotransmitter Receptor Neurotransmitters Nucleus Accumbens Phosphorylation Post-Translational Protein Processing Pre-Clinical Model Predisposition Process Property Public Health Rattus Receptor Signaling Recording of previous events Relapse Rewards Rodent Model Role Self Administration Self-Administered Signal Transduction Site Specificity Stimulus Sucrose Synapses Techniques Testing Training Work addiction alcohol cue alcohol exposure alcohol reinforcement alcohol relapse alcohol seeking behavior alcohol use disorder alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid aniracetam calmodulin-dependent protein kinase II chronic alcohol ingestion drinking drinking behavior experience immunoreactivity inhibitor/antagonist insight neuroadaptation novel receptor reinforcer research study response reward processing synaptic function

项目摘要

The behavioral and molecular mechanisms underlying excessive alcohol drinking behavior and relapse are not fully understood and are vital for mapping the pathological course of alcoholism/dependence. Recent evidence indicates that chronic alcohol consumption leads to strengthening of excitatory synapses in key limbic brain regions that mediate reward and drinking behavior. This strengthening of synapses is highly dependent on the actions and synaptic incorporation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs); fast action ion channel receptors that are activated by the excitatory neurotransmitter glutamate. However, the mechanistic role of enhanced AMPAR signaling in alcohol reinforcement and alcohol-seeking behavior remains unclear. Thus, the proposed experiments in this application seek to elucidate the behavioral and molecular mechanisms that underlie AMPAR-mediated increases in operant alcohol-self-administration and potentiated relapse-like behavior using a preclinical model of high alcohol consumption, the alcoholpreferring (P-) rat. Preliminary data indicate that enhancement of AMPAR signaling by pretreatment with aniracetam (positive allosteric modulator of AMPARs), increases operant alcohol self-administration and potentiates cue-induced reinstatement to alcohol seeking in P-rats, suggesting that enhanced AMPAR activity may be critical in facilitating increased drinking and susceptibility to relapse. Experiments will further characterize the role of enhanced AMPAR signaling in modulating operant self-administration and relapse-like behavior. AMPAR activity can be potentiated by post-translational modification (e.g. phosphorylation of the AMPAR GluR1 subunit amino acid residue 831;pGluR1{831}). Using immunohistochemistry techniques, experiments will map neuroadaptive changes in pGluR1{831} subunits in limbic brain regions after a history of alcohol self-administration or exposure to an alcohol-related cue during cue-induced reinstatement to determine brain regions that may influence enhanced AMPAR-mediated increases in self-administration and alcohol-seeking. We predict to see changes in pGluR1{831} in the nucleus accumbens (self-administration studies) or amygdala (reinstatement studies), and these regions will be targeted to investigate functional neuroanatomical control of enhanced AMPAR activity-mediated facilitation of alcohol self-administration and seeking behavior using aniracetam. Control experiments will address neuroanatomical and reinforcer specificity and non-specific locomotor effects. Lastly we will determine if aniracetam-induced increases in alcohol self-administration and seeking behavior are dependent on Ca2+/calmodulin-dependent protein kinase II (CamKII; known to phosphorylate GluR1 and enhance AMPAR activity) by blocking aniracetam-induced effects during self administration and reinstatement sessions with KN93 (CamKII inhibitor). Key findings from these studies will provide novel insight into AMPAR-related mechanisms in excessive alcohol drinking behavior and vulnerability to relapse.

过度饮酒行为和复发的行为和分子机制尚未完全了解，但对于绘制酗酒/依赖的病理过程至关重要。最近的证据表明，长期饮酒会导致大脑边缘关键区域的兴奋性突触增强，从而调节奖赏和饮酒行为。这种突触的强化高度依赖于 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体 (AMPAR) 的作用和突触掺入；由兴奋性神经递质谷氨酸激活的快速作用离子通道受体。然而，增强的 AMPAR 信号在酒精强化和饮酒行为中的机制作用仍不清楚。因此，本申请中提出的实验旨在使用高酒精消耗的临床前模型（酒精偏好（P-））来阐明 AMPAR 介导的操作性酒精自我管理增加和增强的复发样行为背后的行为和分子机制。鼠。初步数据表明，通过阿尼拉西坦（AMPAR 的正变构调节剂）预处理增强 AMPAR 信号传导，增加操作性酒精自我给药并增强 P 大鼠中提示诱导的酒精寻求恢复，这表明增强的 AMPAR 活性可能对于促进酗酒和旧病复发的可能性增加。实验将进一步表征增强的 AMPAR 信号在调节操作性自我管理和复发样行为中的作用。 AMPAR 活性可以通过翻译后修饰（例如 AMPAR GluR1 亚基氨基酸残基 831；pGluR1{831} 的磷酸化）来增强。使用免疫组织化学技术，实验将绘制自我饮酒史或在线索诱导恢复过程中暴露于酒精相关线索后边缘大脑区域 pGluR1{831} 亚基的神经适应性变化，以确定可能影响 AMPAR 增强的大脑区域介导的自我管理和酒精寻求的增加。我们预测伏隔核（自我给药研究）或杏仁核（恢复研究）中 pGluR1{831} 会发生变化，这些区域将有针对性地研究增强 AMPAR 活性介导的酒精自我给药促进的功能性神经解剖学控制并寻求使用阿尼西坦的行为。对照实验将解决神经解剖学和强化物特异性以及非特异性运动效应。最后，我们将通过阻断阿尼西坦在自我给药期间诱导的作用来确定阿尼西坦诱导的酒精自我给药和寻求行为的增加是否依赖于 Ca2+/钙调蛋白依赖性蛋白激酶 II（CamKII；已知磷酸化 GluR1 并增强 AMPAR 活性），以及KN93（CamKII 抑制剂）恢复疗程。这些研究的主要发现将为过量饮酒行为和复发易感性中与 AMPAR 相关的机制提供新的见解。