Sensitization and Stimulant Self-Administration

描述(申请人提供)：精神运动兴奋剂，如苯丙胺，在人类和实验动物中产生运动和支持自我管理。反复接触这些药物会长期增强它们产生这些效应的能力，称为敏化。因此，了解导致敏感化的神经元事件和作为敏感化基础的神经适应可能对理解药物使用的升级具有特别的影响，药物使用升级的特征是从随意的药物试验向药物渴望和滥用的转变。 众所周知，多巴胺投射到伏隔核，通过影响其他神经递质系统，对苯丙胺产生运动和自我给药行为至关重要。这一事实，再加上反复暴露于苯丙胺使其增加伏隔核胞外多巴胺的能力，表明在致敏动物中观察到的致敏多巴胺神经元反应性与药物的增强追逐和自我给药之间存在重要关系。 利用致敏大鼠增强药物自我给药的模型，拟议的实验将检查可以防止这些旨在获得苯丙胺的致敏反应表达的不同方式。这些实验将集中在使用钙/钙调蛋白依赖的蛋白激酶II(CaMKII)以及条件抑制物(与药物特别不成对的环境刺激)识别的细胞内信号通路。将具体评估它们对增强苯丙胺自我给药和恢复的多巴胺和谷氨酸能神经适应的贡献。 因为CaMKII和条件化抑制剂都选择性地调节对苯丙胺的敏化而非急性反应的表达，所以它们都可能是抑制苯丙胺增强的自我给药和恢复的一个有吸引力的靶点。

DESCRIPTION (provided by applicant): Psychomotor stimulants like amphetamine produce locomotion and support self-administration in humans and laboratory animals. Repeated exposure to these drugs produces long-term enhancements, termed sensitization, in their ability to produce these effects. Understanding the neuronal events that lead to and the neuroadaptation that underlie sensitization may thus have particular bearing for understanding the escalation of drug use that is characteristic of the transition from casual experimentation with drugs to drug craving and abuse. The dopamine projections to the nucleus accumbens are known, via their impact on other neurotransmitter systems, to be critical for the production of locomotor and self-administration behaviors by amphetamine. This, together with the fact that repeated exposure to amphetamine sensitizes its ability to increase extracellular dopamine in the nucleus accumbens, suggests an important relation between sensitized dopamine neuron reactivity and the enhanced pursuit and self-administration of drugs observed in sensitized animals. Using a model of enhanced drug self-administration in the sensitized rat, the proposed experiments will examine different ways in which the expression of these sensitized responses aimed at obtaining amphetamine can be prevented. The experiments will focus on identified intracellular signaling pathways using calcium/calmodulin-dependent protein kinase II (CaMKII), as well as conditioned inhibitors, environmental stimuli specifically unpaired with the drug. Their contribution to dopaminergic and glutamatergic neuroadaptation underlying enhanced amphetamine self-administration and reinstatement will specifically be assessed. Because both CaMKII and conditioned inhibitors selectively regulate the expression of sensitized but not acute responding to amphetamine, they each may represent an attractive target for the inhibition of enhanced amphetamine self-administration and reinstatement.