BIOCHEMICAL AND BEHAVIORAL CONSEQUENCES IN TRANSGENIC MICE

在人类和动物之间有很大的个体差异 对滥用药物的行为、生理和毒理学反应。 对药物的行为反应中的许多个体差异 显示出大量的遗传成分。转基因动物提供了 为了接近三个相互关联的目标：1)基因鉴定 元素赋予细胞类型特定的表达，因此可能允许 将引入的遗传物质定位于适当的大脑区域； 2)阐明产生跨突触基因调控的基因元件 从而允许对引入的基因进行适当的调控表达 材料；以及3)生化和行为后果的确定 关于特定基因的引入或破坏。 多巴胺能系统参与中枢奖赏机制和 突触前和突触后阿片肽的强化和参与 鸦片类药物对系统的影响导致人们对这些系统的关注 在本财年期间。转Mu阿片受体和多巴胺的动物 用行为学方法检测转运蛋白的过度表达。 多巴胺能系统的参与进一步表现为 多巴胺D_1受体基因敲除的评价、生产和评价 多巴胺转运体和VMAT2基因敲除小鼠。Opiat受体亚型 参与镇痛、奖赏和戒断的评估方法为 MUOR基因敲除小鼠的制备与鉴定。这其中的每一个 提供了新的数据，关于 这些基因产物在正常水平和药物诱导下的表达 行为上的改变。

There are large individual differences among humans and animals in behavioral, physiological and toxicological responses to drugs of abuse. Many of these individual differences in behavioral responses to drugs display substantial genetic components. Transgenic animals provide means for approaching three interrelated goals: 1) Identification of gene elements that confer cell-type specific expression and may thus allow targeting of introduced genetic material to appropriate brain regions; 2) Elucidation of gene elements yielding trans-synaptic gene regulation and thus allowing appropriate regulated expression of introduced genetic material; and 3) Ascertainment of biochemical and behavioral consequences of the introduction of or disruption of specific genes. Dopaminergic systems' involvement in central mechanisms of reward and reinforcement, and involvement of pre- and post-synaptic opioid peptide systems in the effects of opiate drugs has led to focus on these systems during this FY. Transgenic animals with mu opiate receptor and dopamine transporter overexpression wre characterized with behavioral assays. Involvement of dopaminergic systems was further characterized by asessment of dopamine D1 receptor knockout, production and assessment of dopamine transporter andVMAT2 knockout mice. Opiat receptor subtype involvement in analgesia, reward and withdrawal were assessed by production and assessment of muOR knockout mice. Each of these asseeements has provided novel data concerning the relationship between exprssion of each of these geneproducts at normal levels and drug-induced behavioral changes.