Appetitive instrumental learning is impaired by inhibition of cAMP-dependent protein kinase within the nucleus accumbens
Appetitive instrumental learning is impaired by inhibition of cAMP-dependent protein kinase within the nucleus accumbens
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DOI：
10.1006/nlme.2000.4002
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发表时间：
2002-01-01
影响因子：
2.7
通讯作者：
Kelley, AE
中科院分区：
文献类型：
--
作者：
Baldwin, AE;Sadeghian, K;Kelley, AE
中脑背外侧核的中型多刺神经元接受来自与动机、认知和感觉过程相关区域的多巴胺能和多巴胺能输入的独特会聚。与食欲学习和药物成瘾等过程相关的丘脑核的长期可塑性可能需要多巴胺D1和谷氨酸N-甲基-D-天冬氨酸（NMDA）受体的共同激活。这一概念意味着细胞内机制可能参与这些长期的神经适应过程。本系列实验研究了蛋白激酶抑制剂的微输注对获得工具性任务的影响，即挤压食物。雄性Sprague-Dawley大鼠双侧植入慢性留置套管，目的是髓核核心。恢复后，对动物进行食物限制，随后进行操作性反应训练。宽碱性丝氨酸/苏氨酸激酶抑制剂H-7（每侧5或27 nmol）剂量依赖性损害学习时，立即输注后测试的第1-4天。Rp-cAMPS是一种cAMP依赖性蛋白激酶（PKA）抑制剂，无论是在第1-4天测试前立即（5或20 nmol）还是测试后立即（10 nmol）输注，Rp-cAMPS也会损害学习。Rp-cAMPS（10 nmol）在测试后1小时输注时也抑制学习，尽管程度低于测试前或测试后立即给药时。PKA刺激剂Sp-cAMPS（5或20 nmol）在测试前输注时也损害学习，表明存在学习所需的最佳PKA活性水平。所用药物均未产生非特异性运动或进食效应。这些结果提供的证据支持参与的核神经元PKA的食欲学习，并建议，这种激酶可能参与长期的变化与此和其他动机为基础的神经适应性过程。(C)2001年，爱思唯尔科学。
The medium spiny neurons of the nucleus accumbens receive a unique convergence of dopaminergic and glutamatergic inputs from regions associated with motivational, cognitive, and sensory processes. Long-term forms of plasticity in the nucleus accumbens associated with such processes as appetitive learning and drug addiction may require coactivation of both dopamine D1 and glutamate N-methyl-D-aspartate (NMDA) receptors. This notion implies that an intracellular mechanism is likely to be involved in these long-term neuroadaptive processes. The present series of experiments examined the effects of intra-accumbens microinfusion of protein kinase inhibitors on acquisition of an instrumental task, lever-pressing for food. Male Sprague-Dawley rats were bilaterally implanted with chronic indwelling cannulae aimed at the nucleus accumbens core. Following recovery, animals were food-restricted and subsequently trained for operant responding. The broad-bascd serine/threonine kinase inhibitor H-7 (5 or 27 nmol per side) dose-dependently impaired learning when infused immediately after testing on days 1-4. Rp-cAMPS, a cAMP-dependent protein kinase (PKA) inhibitor, also impaired learning regardless of whether it was infused immediately before (5 or 20 nmol) or immediately after (10 nmol) testing on days 1-4. Rp-cAMPS (10 nmol) also inhibited learning when infused I h after testing, though to a lesser extent than when administered before or immediately after testing, The PKA stimulator Sp-cAMPS (5 or 20 nmol) also impaired learning when infused before testing, suggesting that there is an optimal level of PKA activity required for learning. None of the drugs used produced nonspecific motor or feeding effects. These results provide evidence supporting the involvement of nucleus accumbens PKA in appetitive learning and suggest that this kinase may be involved in long-term changes associated with this and other motivationally based neuroadaptive processes. (C) 2001 Elsevier Science.