Benneyworth Michael A, Basu Alo C, Coyle Joseph T
Laboratory for Psychiatric and Molecular Neuroscience, McLean Hospital, 115 Mill St., Belmont, MA 02478, USA.
Psychopharmacology (Berl). 2011 Jan;213(1):143-53. doi: 10.1007/s00213-010-2023-4. Epub 2010 Sep 24.
Enhancement of N-methyl-D: -aspartate receptor (NMDAR) activity through its glycine modulatory site (GMS) is a novel therapeutic approach in schizophrenia. Brain concentrations of endogenous GMS agonist D: -serine and antagonist N-acetyl-aspartylglutamate are regulated by serine racemase (SR) and glutamic acid decarboxylase 2 (GCP2), respectively. Using mice genetically, under-expressing these enzymes may clarify the role of NMDAR-mediated neurotransmission in schizophrenia.
We investigated the behavioral effects of two psychotomimetic drugs, the noncompetitive NMDAR antagonist, phencyclidine (PCP; 0, 1.0, 3.0, or 6.0 mg/kg), and the indirect dopamine receptor agonist, amphetamine (AMPH; 0, 1.0, 2.0, or 4.0 mg/kg), in SR -/- and GCP2 -/+ mice. Outcome measures were locomotor activity and prepulse inhibition (PPI) of the acoustic startle reflex. Acute effects of an exogenous GMS antagonist, gavestinel (0, 3.0, or 10.0 mg/kg), on PCP-induced behaviors were examined in wild-type mice for comparison to the mutants with reduced GMS activity.
PCP-induced hyperactivity was increased in GCP2 -/+ mice, and PCP-enhanced startle reactivity was increased in SR -/- mice. PCP disruption of PPI was unaffected in either mutant. In contrast, gavestinel attenuated PCP-induced PPI disruption without effect on baseline PPI or locomotor activity. AMPH effects were similar to controls in both mutant strains.
The results of the PCP experiments demonstrate that convergence of pharmacological and genetic manipulations at NMDARs may confound the predictive validity of these preclinical assays for the effects of GMS activation in schizophrenia. The AMPH data provide additional evidence that hyperdopaminergia in schizophrenia may be distinct from NMDAR hypofunction.
通过其甘氨酸调节位点（GMS）增强N-甲基-D-天冬氨酸受体（NMDAR）活性是精神分裂症的一种新型治疗方法。内源性GMS激动剂D-丝氨酸和拮抗剂N-乙酰天冬氨酰谷氨酸的脑浓度分别由丝氨酸消旋酶（SR）和谷氨酸脱羧酶2（GCP2）调节。利用基因敲低这些酶的小鼠，可能会阐明NMDAR介导的神经传递在精神分裂症中的作用。
我们研究了两种拟精神病药物，即非竞争性NMDAR拮抗剂苯环利定（PCP；0、1.0、3.0或6.0mg/kg）和间接多巴胺受体激动剂苯丙胺（AMPH；0、1.0、2.0或4.0mg/kg）对SR-/-和GCP2-/+小鼠的行为影响。观察指标为自发活动和听觉惊跳反射的前脉冲抑制（PPI）。为了与GMS活性降低的突变体进行比较，在野生型小鼠中检测了外源性GMS拮抗剂加维斯地尔（0、3.0或10.0mg/kg）对PCP诱导行为的急性影响。
PCP诱导的多动在GCP2-/+小鼠中增加，PCP增强的惊跳反应性在SR-/-小鼠中增加。PCP对PPI的破坏在两种突变体中均未受影响。相反，加维斯地尔减轻了PCP诱导的PPI破坏，而对基线PPI或自发活动无影响。两种突变株中AMPH的作用与对照组相似。
PCP实验结果表明，NMDARs处药理学和基因操作的结合可能会混淆这些临床前试验对精神分裂症中GMS激活作用的预测有效性。AMPH数据提供了额外的证据，表明精神分裂症中的多巴胺能亢进可能与NMDAR功能低下不同。
