TRANSGENIC MICE FOR STUDYING DRUGS OF ABUSE

描述：(申请人摘要) 在人类中，海洛因、可卡因和甲基苯丙胺的使用往往成为习惯 正在形成。这被认为在一定程度上要归功于他们强烈的积极情绪。 增强性能。在老鼠身上也观察到了类似的行为， 反复自我给予鸦片或精神刺激剂的小鼠，如果 如果有机会。识别神经解剖底物的努力 这涉及到动物反复服用鸦片类药物或 精神刺激剂依赖于特定脑核的损伤， 微透析和神经药理学操作。海流 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 增强滥用药物的特性。发源于腹侧 被盖区这些多巴胺神经元主要投射到细胞核 伏隔、额叶皮质、嗅结节、杏仁核和隔膜。这个 对腹侧被盖区到伏隔核的输入感兴趣 基于损害和神经药理学的深远影响 操纵伏核中的多巴胺水平对动物的 对鸦片和精神刺激剂的行为反应。尽管多巴胺是 已知与伏隔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 转运体，这些分子中的每一个都在奖励和药物中发挥作用 增强的行为仍有待阐明。转基因小鼠具有 被基因改造为缺乏特定基因产品提供了一种 用来评估该产品在体内的作用的强大手段。在.期间 在之前的资助期间，我们成功地培育了三个品系的小鼠 携带突变的D2或D4受体基因。在这场竞争的延续中 我们提出的应用：(1)培育和测试我们的三个突变小鼠 菌株(N5 D2-/-、N5 D4-/-和D2-/-D4-/-)， 对鸦片类药物和精神刺激剂的生理生化反应； 从多巴胺基因表达水平探讨神经元的可塑性 受体缺陷小鼠，并将这些发现与药物增敏有关； (3)开发携带可诱导靶向载体的新小鼠品系 将允许有条件地表达给定的多巴胺受体。

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.