Canales J J, Capper-Loup C, Hu D, Choe E S, Upadhyay U, Graybiel A M
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, 45 Carleton Street, Cambridge, MA 02139, USA.
Brain. 2002 Oct;125(Pt 10):2353-63. doi: 10.1093/brain/awf239.
Dopamine and glutamate are key neurotransmitters in cortico-basal ganglia loops affecting motor and cognitive function. To examine functional convergence of dopamine and glutamate neurotransmitter systems in the basal ganglia, we evaluated the long-term effects of chronic stimulation of each of these systems on striatal responses to stimulation of the other. First we exposed rats to chronic intermittent cocaine and used early-gene assays to test the responsivity of the striatum to subsequent acute motor cortex stimulation by application of the GABA(A) (gamma-aminobutyric acid alpha subunit) receptor antagonist, picrotoxin. Reciprocally, we studied the effects of chronic intermittent motor cortex stimulation on the capacity for subsequent acute dopaminergic treatments to induce early-gene activation in the striatum. Prior treatment with chronic intermittent cocaine induced motor sensitization and significantly potentiated the striatal expression of Fos-family early genes in response to stimulation of the motor cortex. Contrary to this, chronic intermittent stimulation of the motor cortex down-regulated cocaine-induced gene expression in the striatum, but enhanced striatal gene expression induced by a full D1 receptor agonist (SKF 81297) and did not change the early-gene response elicited by a D2 receptor antagonist (haloperidol). These findings suggests that repeated dopaminergic stimulation produces long-term enhancement of corticostriatal signalling from the motor cortex, amplifying cortically evoked modulation of the basal ganglia. By contrast, persistent stimulation of the motor cortex inhibits cocaine-stimulated signalling in the striatum, but not signalling mediated by individual dopamine receptor sites, suggesting that chronic cortical hyperexcitability produces long-term impairment of dopaminergic activity and compensation at the receptor level. These findings prompt a model of the basal ganglia function as being regulated by opposing homeostatic dopamine-glutamate neurotransmitter interactions. The model provides a framework for analysing the neurological alterations associated with disorders of the basal ganglia and their treatment with pharmacotherapies affecting dopamine and glutamate neurotransmitter systems.
多巴胺和谷氨酸是皮质-基底神经节环路中影响运动和认知功能的关键神经递质。为了研究基底神经节中多巴胺和谷氨酸神经递质系统的功能汇聚，我们评估了长期刺激这些系统中的每一个对纹状体对另一个系统刺激的反应的影响。首先，我们让大鼠长期间歇性接触可卡因，并使用早期基因检测来测试纹状体对随后通过应用GABA(A)（γ-氨基丁酸α亚基）受体拮抗剂印防己毒素进行的急性运动皮层刺激的反应性。相反，我们研究了长期间歇性运动皮层刺激对随后急性多巴胺能治疗诱导纹状体早期基因激活能力的影响。先前用长期间歇性可卡因治疗可诱导运动敏化，并显著增强纹状体中Fos家族早期基因对运动皮层刺激的表达。与此相反，长期间歇性刺激运动皮层可下调纹状体中可卡因诱导的基因表达，但增强了由完全D1受体激动剂（SKF 81297）诱导的纹状体基因表达，并且没有改变由D2受体拮抗剂（氟哌啶醇）引发的早期基因反应。这些发现表明，重复的多巴胺能刺激会导致运动皮层的皮质纹状体信号长期增强，放大了皮层诱发的对基底神经节的调节。相比之下，持续刺激运动皮层会抑制纹状体中可卡因刺激的信号传导，但不会抑制由单个多巴胺受体位点介导的信号传导，这表明慢性皮层过度兴奋会导致多巴胺能活动的长期损害以及受体水平的代偿。这些发现提示了一种基底神经节功能模型，该模型由相反的稳态多巴胺-谷氨酸神经递质相互作用调节。该模型为分析与基底神经节疾病相关的神经学改变以及用影响多巴胺和谷氨酸神经递质系统的药物疗法进行治疗提供了一个框架。
