Pharmacological stimulation of NMDA receptors via co-agonist site suppresses fMRI response to phencyclidine in the rat
Pharmacological stimulation of NMDA receptors via co-agonist site suppresses fMRI response to phencyclidine in the rat
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DOI：
10.1007/s00213-008-1271-z
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发表时间：
2008-12-01
影响因子：
3.4
通讯作者：
Bifone, Angelo
中科院分区：
文献类型：
--
作者：
Gozzi, Alessandro;Herdon, Hugh;Bifone, Angelo
越来越多的实验证据表明，N-甲基-d-天冬氨酸受体(NMDAR)功能受损可能是精神分裂症的关键病理生理决定因素。NMDA复合体变构甘氨酸(Gly)结合部位的激动剂可以促进NMDAR的活性，这一策略可以为这种疾病提供治疗效果。NMDAR拮抗剂如苯环利定(PCP)可以引起类似于精神分裂症的精神症状和分离症状，因此被广泛用于实验以损害活体NMDA神经传递。在本研究中，我们使用药物磁共振成像(PhMRI)来研究NMDAR甘氨酸位点的内源性和外源性激动剂对急性PCP刺激诱导的大鼠脑激活的时空模式的调制作用。被研究的药物是NMDAR甘氨酸位点的内源性激动剂d-丝氨酸和SSR504734，SSR504734是一种有效的Gly转运体1型(GlyT-1)抑制剂，可以通过增加突触Gly水平来增强NMDAR的功能。急性给予PCP可强烈而持续地激活离散的皮质-边缘-丘脑回路。预先给予d-丝氨酸(1g/kg)或SSR504734(10 mg/kg)可完全抑制PCP诱导的功能激活。这一效应伴随着微弱但持续的失活，特别是在大脑皮层。这些发现表明，通过甘氨酸共激动剂位点刺激NMDAR的药物可以增强活着的大脑中的NMDAR活性，并证实了这类药物有选择地增强精神分裂症患者NMDAR神经传递的潜力。
Increasing experimental evidence suggests that impaired N-methyl-d-aspartic acid (NMDA) receptor (NMDAr) function could be a key pathophysiological determinant of schizophrenia. Agonists at the allosteric glycine (Gly) binding site of the NMDA complex can promote NMDAr activity, a strategy that could provide therapeutic efficacy for the disorder. NMDAr antagonists like phencyclidine (PCP) can induce psychotic and dissociative symptoms similar to those observed in schizophrenia and are therefore widely used experimentally to impair NMDA neurotransmission in vivo.In the present study, we used pharmacological magnetic resonance imaging (phMRI) to investigate the modulatory effects of endogenous and exogenous agonists at the NMDAr Gly site on the spatiotemporal patterns of brain activation induced by acute PCP challenge in the rat. The drugs investigated were d-serine, an endogenous agonist of the NMDAr Gly site, and SSR504734, a potent Gly transporter type 1 (GlyT-1) inhibitor that can potentiate NMDAr function by increasing synaptic levels of Gly.Acute administration of PCP induced robust and sustained activation of discrete cortico-limbo-thalamic circuits. Pretreatment with d-serine (1 g/kg) or SSR504734 (10 mg/kg) completely inhibited PCP-induced functional activation. This effect was accompanied by weak but sustained deactivation particularly in cortical areas.These findings suggest that agents that stimulate NMDAr via Gly co-agonist site can potentiate NMDAr activity in the living brain and corroborate the potential for this class of drugs to provide selective enhancement of NMDAr neurotransmission in schizophrenia.