Heusner Carrie L, Palmiter Richard D
Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.
J Neurosci. 2005 Jul 13;25(28):6651-7. doi: 10.1523/JNEUROSCI.1474-05.2005.
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 D1 receptors (D1Rs) and D2 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.
多巴胺与谷氨酸在边缘脑区的相互作用介导了与精神兴奋剂相关的行为，精神兴奋剂部分作用于增加D1受体（D1Rs）和D2受体处的多巴胺信号。许多成瘾行为是习得性关联的结果，并且已证明NMDA受体激活对这些行为很重要。我们假设，如果精神兴奋剂的成瘾特性需要含多巴胺受体的细胞中NMDA受体激活，那么含D1R的细胞中NMDA受体活性降低的小鼠对这些药物的长期行为变化将减弱。我们构建了一个小鼠品系，其中含D1R的细胞表达一种NR1 NMDA受体亚基，该亚基在孔道中有一个突变，可减少钙内流。在含D1R的细胞中表达突变型NMDA受体的小鼠具有正常的基础活动，并且在急性给予苯丙胺或可卡因时表现出类似的运动活动增加。然而，突变小鼠对重复给予可卡因未能表现出运动敏化。此外，这些小鼠对可卡因形成条件性位置偏好的能力也降低。这些数据表明，含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行为表现所必需的。
