Activation of metabotropic glutamate 2/3 receptors reverses the effects of NMDA receptor hypofunction on prefrontal cortex unit activity in awake rats
Activation of metabotropic glutamate 2/3 receptors reverses the effects of NMDA receptor hypofunction on prefrontal cortex unit activity in awake rats
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DOI：
10.1152/jn.00875.2004
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发表时间：
2005-04-01
影响因子：
2.5
通讯作者：
Moghaddam, B
中科院分区：
文献类型：
--
作者：
Homayoun, L;Jackson, ME;Moghaddam, B
全身暴露于N-甲基-D-天冬氨酸(NMDA)受体拮抗剂可导致精神病和前额叶皮质(PFC)依赖的行为障碍。代谢型谷氨酸2/3(mGlu2/3)受体激动剂可改善NMDA拮抗剂对人类和实验动物的不良行为影响，被认为是治疗精神分裂症某些症状的新方法。尽管有令人信服的行为数据，但mGlu2/3受体功能增强减弱NMDA受体功能低下的影响的细胞机制仍不清楚。在自由活动的大鼠上，我们记录了内侧PFC(初步)单位对NMDA拮抗剂MK801的反应，并评估了mGlu2/3受体激动剂LY354740治疗前后对这一反应的剂量依赖效应。在记录过程中测量了NMDA受体拮抗剂诱导的行为刻板印象，因为它可能与这种治疗的拟精神属性有关，并依赖于PFC的功能完整性。在大多数PFC神经元中，全身应用MK801增加了自发放电频率，降低了棘波序列的变异性，并扰乱了自发爆发的模式。单独给予LY354740(1、3和10 mg/kg)可在最大剂量下降低PFC神经元的自发活动。LY354740治疗前后可阻断MK801诱发的放电机会。突发性活动，以及尖峰活动的变异性。这些生理变化与LY354740减少MK801诱导的行为刻板印象不谋而合。这些结果表明，mGlu2/3受体的激活减轻了NMDA受体功能低下对PFC神经元自发放电和爆发的干扰作用。这一机制可能为mGlu2/3激动剂逆转NMDA拮抗剂诱导的行为提供了生理基础。
Systemic exposure to N-methyl-D-aspartate (NMDA) receptor antagonists can lead to psychosis and prefrontal cortex (PFC)-dependent behavioral impairments. Agonists of metabotropic glutamate 2/3 (mGlu2/3) receptors ameliorate the adverse behavioral effects of NMDA antagonists in humans and laboratory animals, and are being considered as a novel treatment for some symptoms of schizophrenia. Despite the compelling behavioral data, the cellular mechanisms by which potentiation of mGlu2/3 receptor function attenuates the effects of NMDA receptor hypofunction remain unclear. In freely moving rats, we recorded the response of medial PFC (prelimbic) single units to treatment with the NMDA antagonist MK801 and assessed the dose-dependent effects of pre- or posttreatment with the mGlu2/3 receptor agonist LY354740 on this response. NMDA receptor antagonist-induced behavioral stereotypy was measured during recording because it may relate to the psychotomimetic properties of this treatment and is dependent on the functional integrity of the PFC. In most PFC neurons, systemic administration of MK801 increased the spontaneous firing rate, decreased the variability of spike trains, and disrupted patterns of spontaneous bursts. Given alone, LY354740 (1, 3, and 10 mg/kg) decreased spontaneous activity of PFC neurons at the highest dose. Pre- or posttreatment with LY354740 blocked MK801-induced chances on firing rate. burst activity, and variability of spike activity. These physiological changes coincided with a reduction in MK801-induced behavioral stereotypy by LY354740. These data indicate that activation of mGlu2/3 receptors reduces the disruptive effects of NMDA receptor hypofunction on the spontaneous spike activity and bursting of PFC neurons. This mechanism may provide a physiological basis for reversal of NMDA antagonist-induced behaviors by mGlu2/3 agonists.