Expression of mutant NMDA receptors in dopamine D1 receptor-containing cells prevents cocaine sensitization and decreases cocaine preference
Expression of mutant NMDA receptors in dopamine D1 receptor-containing cells prevents cocaine sensitization and decreases cocaine preference
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DOI：
10.1523/jneurosci.1474-05.2005
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发表时间：
2005-07-13
影响因子：
5.3
通讯作者：
Palmiter, RD
中科院分区：
文献类型：
--
作者：
Heusner, CL;Palmiter, RD
边缘脑区域多巴胺和谷氨酸的相互作用介导与精神兴奋剂相关的行为，其部分作用是增加 D-1 受体 (D1R) 和 D-2 受体的多巴胺信号传导。许多成瘾行为是习得性关联的结果，NMDA 受体激活已被证明对这些行为很重要。我们假设，如果精神兴奋剂的成瘾特性需要多巴胺受体细胞中 NMDA 受体的激活，那么 D1R 细胞中 NMDA 受体活性降低的小鼠就会减弱这些药物的长期行为变化。我们构建了一个小鼠品系，其中含有 D1R 的细胞表达 NR1 NMDA 受体亚基，该受体亚基在孔中含有减少钙通量的突变。在含有 D1R 的细胞中表达突变型 NMDA 受体的小鼠具有正常的基础活性，并且在用急性苯丙胺或可卡因治疗时表现出类似的运动活性增加。然而，突变小鼠未能表现出对重复给予可卡因的运动敏感性。此外，这些小鼠对可卡因形成条件性位置偏好的能力也有所下降。这些数据表明，含有 D1R 的细胞中完整的 NMDA 受体信号传导是与重复药物暴露相关的行为表现所必需的。
The interaction of dopamine and glutamate in limbic brain regions mediates behaviors associated with psychostimulants, which act in part to increase dopamine signaling at both D-1 receptors (D1Rs) and D-2 receptors. Many addictive behaviors are a result of learned associations, and NMDA receptor activation has been shown to be important for these behaviors. We hypothesized that if NMDA receptor activation in dopamine receptor-containing cells is required for the addictive properties of psychostimulants, then mice with reduced NMDA receptor activity in D1R-containing cells would have attenuated long-term behavioral changes to these drugs. We generated a mouse line in which D1R-containing cells express an NR1 NMDA receptor subunit containing a mutation in the pore that reduces calcium flux. Mice expressing the mutant NMDA receptors in D1R-containing cells have normal basal activity and display similar increases in locomotor activity when treated with acute amphetamine or cocaine. However, the mutant mice fail to display locomotor sensitization to repeated cocaine administration. In addition, these mice also have a decreased ability to form a conditioned place preference to cocaine. These data suggest that intact NMDA receptor signaling in D1R-containing cells is required for the manifestation of behaviors associated with repeated drug exposure.