Role of different monoamine receptors controlling MK-801-induced release of serotonin and glutamate in the medial prefrontal cortex: relevance for antipsychotic action
Role of different monoamine receptors controlling MK-801-induced release of serotonin and glutamate in the medial prefrontal cortex: relevance for antipsychotic action
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DOI：
10.1017/s1461145708009267
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发表时间：
2009-05-01
影响因子：
4.8
通讯作者：
Adell, Albert
中科院分区：
文献类型：
--
作者：
Lopez-Gil, Xavier;Artigas, Francesc;Adell, Albert
多项研究表明，全身给予N-甲基-D-天冬氨酸（NMDA）受体拮抗剂会增加内侧前额叶皮质（mPFC）中5-羟色胺（5-HT）和谷氨酸的释放。以前，我们表明，灌注氯氮平在mPFC防止MK-801诱导的细胞外谷氨酸和5-HT的增加，而氟哌啶醇阻断MK-801对谷氨酸的影响。研究不同的单胺能受体在细胞内的作用，（氯氮平和氟哌啶醇表现出不同的亲和力）对这些作用的影响，在这里，我们使用体内微透析来检查局部阻断多巴胺D-2，5-HT 2A和α（1）-肾上腺素能受体以及激动mPFC中的多巴胺D-1和5-HT 1A受体对MK-801引起的谷氨酸和5-HT流出增加的作用。结果表明，M100907（5-HT 2A拮抗剂）、BAY x 3702（5-HT 1A激动剂）和哌唑嗪（α（1）-肾上腺素能拮抗剂）可阻断MK-801诱导的mPFC中5-HT和谷氨酸的增加。然而，雷氯必利、依替氯必利（多巴胺D-2拮抗剂）和SKF-38393（多巴胺D-1激动剂）能够阻止MK-801引起的谷氨酸外排增加（但不能阻止5-HT外排增加）。我们建议，D-2受体拮抗剂和D-1激动剂将主要作用于mPFC的GABA能中间神经元的亚群，从而导致增强的皮质抑制，防止过度的GABA能传递。另一方面，非典型抗精神病药物可能进一步作用于锥体细胞（包括向中缝背核投射的锥体细胞）中存在的5-HT 2A、5-HT 1A和α（1）-肾上腺素受体，这将直接抑制这些细胞的过度兴奋性。
Several studies have demonstrated that systemically administered N-methyl-D-aspartate (NMDA) receptor antagonists increase serotonin (5-HT) and glutamate release in the medial prefrontal cortex (mPFC). Previously we showed that the perfusion of clozapine in the mPFC prevented the MK-801-induced increase in extracellular glutamate and 5-HT whereas haloperidol blocked only the effect of MK-801 on glutamate. To study the contribution of different monoaminergic receptors (for which clozapine and haloperidol exhibit distinct affinities) to these effects, here we used in-vivo microdialysis to examine the role of local blockade of dopamine D-2, 5-HT2A and alpha(1)-adrenergic receptors as well as agonism at dopamine D-1 and 5-HT1A receptors in the mPFC on the increased efflux of glutamate and 5-HT elicited by MK-801. The results show that M100907 (5-HT2A antagonist), BAY x 3702 (5-HT1A agonist) and prazosin (alpha(1)-adrenergic antagonist) blocked the MK-801-induced increase of 5-HT and glutamate in the mPFC. However, raclopride, eticlopride (dopamine D-2 antagonists) and SKF-38393 (dopamine D-1 agonist) were able to prevent the increased efflux of glutamate (but not that of 5-HT) elicited by MK-801. We propose that D-2 receptor antagonists and D-1 agonists would act predominantly on a subpopulation of GABAergic interneurons of the mPFC, thus leading to an enhanced cortical inhibition that would prevent an excessive glutamatergic transmission. On the other hand, atypical antipsychotic drugs might further act upon 5-HT2A, 5-HT1A and alpha(1)-adrenoceptors present in pyramidal cells (including those projecting to the dorsal raphe nucleus), which would directly inhibit an excessive excitability of these cells.