TRANSGENIC MICE FOR STUDYING DRUGS OF ABUSE

描述：（申请人摘要） 在人类中，使用海洛因、可卡因和甲基苯丙胺往往成为习惯 成形 这被认为是由于，在某种程度上， 增强性能 在大鼠中也观察到了类似的行为， 小鼠将反复自我管理阿片类药物或精神兴奋剂， 只要有机会 努力识别神经解剖学基质 涉及动物反复服用鸦片剂或 精神兴奋剂依赖于特定脑核团的损伤， 微透析和神经药理学操作。 当前 这一领域的解释是中皮质边缘多巴胺神经元 在很大程度上，负责调解许多积极的 加强滥用药物的性质。 起源于腹侧 在被盖区，这些多巴胺神经元主要投射到核 额叶皮质，嗅结节，杏仁核和隔。 的 对腹侧被盖区到丘脑腹侧核的输入的兴趣是 基于损伤和神经药理学 操纵多巴胺水平的神经核对动物的 对鸦片和精神兴奋剂的行为反应 虽然多巴胺是 已知其与脑桥核中的少量蛋白质相互作用， 包括多巴胺受体家族的成员和多巴胺 转运蛋白，这些分子中的每一个在奖励和药物中发挥的作用， 强化行为仍有待阐明。 转基因小鼠 被基因改变以缺乏特定的基因产物， 评估该产品在体内作用的有力手段。 期间 在前一个资助期内，我们成功地培育了三种小鼠， 携带突变的D2或D4受体基因。 在这场竞争的延续中 我们的应用是：（1）培育和测试我们的三个突变小鼠 菌株（N5 D2-/-、N5 D4-/-和D2-/-D4-/-）的行为， 对阿片类药物和精神兴奋剂的生理和生化反应;（2） 在我们的多巴胺基因表达水平上探索神经元可塑性 受体缺陷小鼠，并将这些发现与药物致敏性联系起来; (3)开发携带可诱导靶向载体的新小鼠品系， 将允许给定多巴胺受体的条件表达。

DESCRIPTION: (Applicant's Abstract) In humans the use of heroin, cocaine and methamphetamine often becomes habit forming. This is thought to be due, in part, to their strong positive reinforcing properties. Similar behavior has also been observed in rats and mice who will repeatedly self-administer opiates or psychostimulants if given the opportunity. Efforts to identify the neuroanatomical substrates that involve an animal's repeated administration of an opiate or a psychostimulant have relied on lesioning of specific brain nuclei, microdialysis and neuro-pharmacological manipulations. The current interpretation in this field is that the mesocorticolimbic dopamine neurons are, to a large extent, responsible for mediating many of the positive reinforcing properties of abused drugs. Originating in the ventral tegmental area these dopamine neurons project primarily to the nucleus accumbens, frontal cortex, olfactory tubercle, amygdala, and septum. The interest in the ventral tegmental area's input to the nucleus accumbens is based on the profound effects that lesioning and neuropharmacological manipulation of dopamine levels in the nucleus accumbens have on an animal's behavioral response to opiates and psychostimulants. Although dopamine is known to interact with a small number of proteins in the nucleus accumbens, including members of the dopamine receptor family and the dopamine transporter, role that each of these molecules play in rewarding and drug reinforced behavior remains to be elucidated. Transgenic mice that have been genetically altered to lack a particular gene product provide a powerful means by which to assess the role of that product in vivo. During the preceding funding period we successfully produced three strains of mice that carry mutated D2 or D4 receptor genes. In this competing continuation application we propose to: (1) Breed and test our three mutant mouse strains (N5 D2-/-, N5 D4-/- and D2-/-D4-/-) for their behavioral, physiological and biochemical responses to opiates and psychostimulants; (2) Explore neuronal plasticity at the level of gene expression in our dopamine receptor-deficient mice and relate these findings to drug sensitization; and (3) Develop new mouse strains that carry inducible targeting vectors that will permit the conditional expression of a given dopamine receptor.