Sensitization and Stimulant Self-Administration

描述（由申请人提供）：精神兴奋剂，如安非他明，在人类和实验室动物中产生运动并支持自我给药。反复接触这些药物会产生长期的增强作用，称为致敏作用，增强其产生这些作用的能力。因此，了解导致致敏的神经元事件和作为致敏基础的神经适应可能对理解药物使用的升级具有特别的意义，药物使用的升级是从随意尝试药物到药物渴望和滥用的过渡的特征。 已知多巴胺投射到丘脑核，通过它们对其他神经递质系统的影响，对安非他明产生运动和自我给药行为至关重要。这一点，再加上事实上，反复暴露于安非他明敏化其能力，以增加细胞外多巴胺在核内，表明一个重要的关系，敏化多巴胺神经元的反应性和增强的追求和自我管理的药物中观察到的致敏动物。 使用模型的增强药物自我管理的致敏大鼠，拟议的实验将检查不同的方式，这些致敏反应的表达，旨在获得安非他明可以被阻止。实验将集中在使用钙/钙调蛋白依赖性蛋白激酶II（CaMKII），以及条件抑制剂，环境刺激，特别是与药物不配对确定的细胞内信号通路。他们的贡献，多巴胺能和多巴胺能神经适应增强安非他明自我管理和恢复将具体评估。 因为CaMKII和条件抑制剂选择性地调节致敏的表达，但不是急性响应安非他明，他们每个人都可能代表一个有吸引力的目标，增强安非他明自我管理和恢复的抑制。

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.