Behavioural adaptations to addictive drugs in mice lacking the NMDA receptor ε1 subunit
Behavioural adaptations to addictive drugs in mice lacking the NMDA receptor ε1 subunit
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DOI：
10.1111/j.1460-9568.2004.03086.x
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发表时间：
2004-01-01
影响因子：
3.4
通讯作者：
Nabeshima, T
中科院分区：
文献类型：
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作者：
Miyamoto, Y;Yamada, K;Nabeshima, T
N-甲基-D-天冬氨酸（N-methyl-D-aspartate，NMDA）受体是谷氨酸受体（glutamate receptor，GluR）的一个亚型，由GluR β亚基（NR 1）与GluR β亚基（GluR β 1 -4; NR 2A-D）组装而成，在兴奋性神经传递、突触可塑性和脑发育中起重要作用。最近的药理学研究也表明NMDA受体在药物成瘾中的作用。在本研究中，我们研究了缺乏NMDA受体GluRepsilon 1亚基的小鼠对成瘾药物如苯环利定（PCP）、甲基苯丙胺（MAP）和吗啡（莫尔）的行为适应。如通过[H-3]MK-的减少所证明的，801结合在放射自显影受体结合试验GluRepsilon 1突变小鼠表现出急性PCP和MAP诱导的过度运动的衰减。以低剂量（而非高剂量）重复使用五氯苯酚和MAP也可抑制致敏作用的发展。在GluRepsilon 1突变小鼠中，MOR诱导的镇痛耐受和纳洛酮诱导的莫尔戒断症状的发展减弱。在位置条件反射试验中，PCP诱导的位置厌恶在幼稚小鼠和位置偏好在PCP预处理的小鼠，以及MOR诱导的位置偏好，减少，而MAP诱导的位置偏好在GluRepsilon 1突变小鼠不受影响。这些发现提供了遗传学证据，表明含有GluRepsilon 1亚基的NMDA受体参与了药物成瘾的某些方面。
N-methyl-D-aspartate (NMDA) receptors, a subtype of glutamate receptors (GluRs) formed by assembly of the GluRepsilon subunit (called NR1 in rats) with any one of four GluRepsilon subunits (GluRepsilon1-4; NR2A-D), play an important role in excitatory neurotransmission, synaptic plasticity and brain development. Recent pharmacological studies have also indicated a role for NMDA receptors in drug addiction. In the present study, we investigated the behavioural adaptations to addictive drugs such as phencyclidine (PCP), methamphetamine (MAP) and morphine (MOR) in mice lacking the GluRepsilon1 subunit of the NMDA receptor GluRepsilon1 mutant mice exhibited a malfunction of NMDA receptors, as evidenced by the reduction of [H-3]MK-801 binding in an autoradiographic receptor binding assay GluRepsilon1 mutant mice showed an attenuation of acute PCP- and MAP-induced hyperlocomotion. The development of sensitization by repeated treatment with PCP and MAP at a low, but not high, dose was also suppressed. The development of MOR-induced analgesic tolerance and naloxone-precipitated MOR withdrawal symptoms were attenuated in GluRepsilon1 mutant mice. In the place conditioning test, PCP-induced place aversion in naive mice and place preference in PCP-pretreated mice, as well as MOR-induced place preference, were diminished whereas MAP-induced place preference was not affected in GluRepsilon1 mutant mice. These findings provide genetic evidence that GluRepsilon1 subunit-containing NMDA receptors are involved in certain aspects of drug addiction.