Role of Calcium in Cocaine-Induced Sensitization

滥用精神兴奋剂，如可卡因已成为一种医疗和社会疾病，在这个国家，有必要确定的细胞和分子机制的行为影响，导致这些药物的重复管理。研究这些机制的原因之一是行为敏化现象，这是一个渐进的和持久的增强运动和刻板的活动，在大鼠，结果是重复间歇性精神兴奋剂管理。此外，研究表明，反复服用药物后，神经生理学发生了变化，导致了对药物的渴望。因此，研究这些潜在的神经生理学改变可以帮助阐明神经元可塑性的一般机制。有证据表明，钙和钙介导的第二信使系统在精神兴奋剂诱导的可塑性的影响中发挥重要作用。已显示全身注射L-型钙通道拮抗剂会损害胭脂红的行为激活作用，而VTA下给予L-型钙通道激动剂可模拟可卡因行为敏化的诱导期。拟议的研究将通过检查钙信号分子在可卡因诱导的致敏反应中的作用来扩展这些发现。这将通过两种方式实现。首先，在全身给予可卡因之前，大鼠将接受L型钙通道、钙调蛋白或CaMK II拮抗剂的VTA下或黑质下注射，并监测行为。在两周的戒断期后，所有大鼠将接受可卡因的全身激发注射，并监测它们的行为以确定抑制钙通过L型通道流入或抑制钙信号传导对可卡因致敏的影响。第二，大鼠将接受急性或重复可卡因，并使用免疫标记技术测量VTA和黑质中钙调蛋白或CaMK II的相对丰度。

Abuse of psychostimulants such as cocaine has become a medical and social ill in this country, making it necessary to identify the cellular and molecular mechanisms underlying the behavioral effects that result from repeated administration of these drugs. Among the reasons to study these mechanisms is the phenomenon of behavioral sensitization which is a progressive and enduring augmentation of locomotor and stereotyped activity in rats that results from repeated intermittent psychostimulant administration. Furthermore, studies suggest that following repeated drug taking there are changes in neurophysiology that contribute to drug craving. Thus, investigating these underlying neurophysiological alterations can help elucidate mechanisms of neuronal plasticity in general. Evidence indicates that calcium and calcium-mediated second messenger systems play an important role in the effects of psychostimulant-induced plasticity. Systemic injections of L-type calcium channel antagonists have been shown to impair the behavioral activating effects of carmine while infra-VTA administration of an L- type calcium channel agonist can mimic the induction phase of behavioral sensitization to cocaine. The proposed research will expand on these findings by examining the role of calcium signaling molecules in the initiation of cocained-induced sensitization. This will be accomplished in two ways. First, rats will receive infra-VTA or infra- nigral injections of antagonists of either L-type calcium channels, calmodulin, or CaMKII prior to systemic administration of cocaine, and behavior will be monitored. Following a two week withdrawal period all rats will receive a systemic challenge injection of cocaine and their behavior will be monitored to determine the effects of inhibiting calcium influx through L-type channels or inhibiting calcium signaling on sensitization to cocaine. Second, rats will receive either acute or repeated cocaine and relative abundance of either calmodulin or CaMKII will be measured in the VTA and substantia nigra using immunolabeling techniques.