MECHANISM OF SENSITIZATION TO COCAINE

尽管以神经递质多巴胺为核心的大量关于药物滥用的细胞和分子方面的精美工作已经发展出来，但神经肽代表着一个与药物成瘾有关的尚未被研究的领域。神经肽可以直接和/或间接影响哺乳动物大脑的多巴胺能网络的输出。本项目将侧重于神经肽P物质(和神经激肽A)在对可卡因的致敏运动和神经化学反应的发展和/或表达中所起的作用。我们推测，这些速激肽在基底节内起着稳态作用，以防止对可卡因敏感的啮齿动物过度运动输出。第一个和第二个特定目标将评估高选择性非肽神经激肽受体拮抗剂在对可卡因的渐进性和持久性运动敏化发展中的作用。第三个具体目的是研究这些高选择性拮抗剂对多巴胺能终末区、中脑黑质致密区和腹侧被盖区多巴胺能终末区和伏隔核多巴胺能区多巴胺和谷氨酸释放的影响。神经激肽受体拮抗剂将通过微透析探头在大脑内注入。第四个特定目的是在渐进和持久的治疗下，提供可卡因致敏大鼠的底物P和神经激动素A的组织肽水平。来自这一目标的数据补充了AIMS I和AIMS II中从动物身上获得的神经肽和受体mRNA水平。这些研究将提供强有力的行为和神经化学证据，支持速激肽在可卡因致敏反应中的作用。对可卡因敏化的神经生物学的了解与人类成瘾的管理有关，因为敏化被认为是维持对可卡因和其他药物上瘾的人寻求药物行为的一种机制。

Although a large body of elegant work has developed on cellular and molecular aspects of drug abuse with the neurotransmitter dopamine at its core, the neuropeptides represent an area that has not been studied in relation to drug addiction. Neuropeptides can exert direct and/or indirect effects on the output of the dopaminergic network of the mammalian brain. The present project will focus on the role played by the neuropeptide substance P (and neurokinin A) on the development and/or expression of sensitized locomotor and neurochemical responses to cocaine. We hypothesize that these tachykinin peptides serve homeostatic functions within the basal ganglia to prevent excessive locomotor output in rodents sensitized to cocaine. The first and second specific aims will assess the effect of highly selective non-peptide neurokinin receptor antagonists on the development of progressive and enduring locomotor sensitization to cocaine. The third specific aim will examine the effect of these highly selective antagonists on the sensitized pattern of dopamine and glutamate release in dopaminergic terminal field areas of the caudate-putamen and the nucleus accumbens as well as in dopaminergic cell body areas of the midbrain substantia nigra compacta and the ventral tegmental area. The neurokinin receptor antagonists will be infused intracerebrally through the microdialysis probe. The fourth specific aim provides tissue peptide levels for substrate P and neurokinin A from rats sensitized to cocaine under progressive and enduring treatments. The data from this aim complements neuropeptide and receptor mRNA levels obtained from animals in aims I and II. These studies will provide strong behavioral and neurochemical evidence supporting a role for tachykinin peptides in sensitized responses to cocaine. An understanding of the neurobiology of sensitization to cocaine is relevant to the management of addiction in humans because sensitization is implicated as a mechanism sustaining drug-seeking behavior in humans addicted to cocaine and other drugs.