Appetitive instrumental learning requires coincident activation of NMDA and dopamine D1 receptors within the medial prefrontal cortex
Appetitive instrumental learning requires coincident activation of NMDA and dopamine D1 receptors within the medial prefrontal cortex
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DOI：
10.1523/jneurosci.22-03-01063.2002
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发表时间：
2002-02-01
影响因子：
5.3
通讯作者：
Kelley, AE
中科院分区：
文献类型：
--
作者：
Baldwin, AE;Sadeghian, K;Kelley, AE
通过其在认知、记忆和情感中的复杂作用，哺乳动物的前额叶皮层被认为有助于组织适应性行为。在本研究中，我们研究了在适应性工具学习的发展过程中，大鼠前额叶皮层内的多巴胺能D1和多巴胺能NMDA受体的作用。在内侧前额叶皮质植入双侧留置套管的饥饿大鼠接受训练，以挤压食物。输注选择性D1拮抗剂SCH-23390（0.15、0.3、3.0 nmol）可剂量依赖性地损害该行为的获得。高剂量也损害了这一任务的表达。最低剂量的SCH 23390与低剂量的NMDA拮抗剂AP-5（0.5 nmol）联合输注（单独输注时，两者均对学习无影响）可有效降低获得反应的能力。用选择性PKA抑制剂Rp-cAMPS抑制细胞内蛋白激酶A也破坏了获得，表明PKA是D1-NMDA受体相互作用的细胞内底物。在对照实验中，损害学习的药物输注并不影响食物摄入或运动，这表明对学习有特定影响。我们假设，D1-NMDA受体激活及其转录的后果，在多个站点的分布式皮质纹状体网络的同时检测，可能代表一个保守的分子机制，工具学习。
Through its complex role in cognition, memory, and emotion, the mammalian prefrontal cortex is thought to contribute to the organization of adaptive behavioral actions. In the present studies we examined the role of dopaminergic D1 and glutamatergic NMDA receptors within the prefrontal cortex of the rat during the development of adaptive instrumental learning. Hungry rats with bilateral indwelling cannulas aimed at the medial prefrontal cortex were trained to lever-press for food. Infusion of the selective D1 antagonist SCH-23390 (0.15, 0.3, 3.0 nmol) dose-dependently impaired acquisition of this behavior. Higher doses also impaired expression of this task. Co-infusion of the lowest dose of SCH 23390 with a low dose of the NMDA antagonist AP-5 (0.5 nmol), each of which had no effect on learning when infused alone, potently reduced the ability to acquire the response. Inhibition of intracellular protein kinase A with the selective PKA inhibitor Rp-cAMPS also disrupted acquisition, suggesting that PKA is an intracellular substrate for a D1-NMDA receptor interaction. In control experiments, drug infusions that impaired learning did not affect food intake or locomotion, suggesting a specific effect on learning. We hypothesize that coincident detection of D1-NMDA receptor activation and its transcriptional consequences, within multiple sites of a distributed corticostriatal network, may represent a conserved molecular mechanism for instrumental learning.