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首页> 外文期刊>Addiction biology >N-Methyl-d-aspartate receptor co-agonist availability affects behavioral and neurochemical responses to cocaine: insights into comorbid schizophrenia and substance abuse
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N-Methyl-d-aspartate receptor co-agonist availability affects behavioral and neurochemical responses to cocaine: insights into comorbid schizophrenia and substance abuse

机译：N-甲基-D-天冬氨酸受体共激动剂可用性会影响对可卡因的行为和神经化学反应：洞察同型精神分裂症和物质滥用

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摘要

Both schizophrenia (SZ) and substance abuse (SA) exhibit significant heritability. Moreover, N-methyl-d-aspartate receptors (NMDARs) have been implicated in the pathophysiology of both SZ and SA. We hypothesize that the high prevalence of comorbid SA in SZ is due to dysfunction of NMDARs caused by shared risk genes. We used transgenic mice with a null mutation of the gene encoding serine racemase (SR), the enzyme that synthesizes the NMDAR co-agonist d-serine and an established risk gene for SZ, to recreate the pathology of SZ. We determined the effect of NMDAR hypofunction resulting from the absence of d-serine on motivated behavior by using intracranial self-stimulation and neurotransmitter release in the nucleus accumbens by using in vivo microdialysis. Compared with wild-type mice, SR-/- mice exhibited similar baseline intracranial self-stimulation thresholds but were less sensitive to the threshold-lowering (rewarding) and the performance-elevating (stimulant) effects of cocaine. While basal dopamine (DA) and glutamate release were elevated in the nucleus accumbens of SR-/- mice, cocaine-induced increases in DA and glutamate release were blunted. gamma-Amino-butyric acid efflux was unaffected in the SR-/- mice. Together, these findings suggest that the impaired NMDAR function and a consequent decrease in sensitivity to cocaine effects on behavior are mediated by blunted DA and glutamate responses normally triggered by the drug. Projected to humans, NMDAR hypofunction due to mutations in SR or other genes impacting glutamatergic function in SZ may render abused substances less potent and effective, thus requiring higher doses to achieve a hedonic response, resulting in elevated drug exposure and increased dependence/addiction.
机译：精神分裂症（SZ）和物质滥用（SA）表现出显着的遗传性。此外，N-甲基-D-天冬氨酸受体（NMDARS）涉及SZ和SA的病理生理学。我们假设SZ中同源式SA的高患病率是由于共同风险基因引起的氮虫功能障碍。我们使用了具有编码丝氨酸的基因突变的转基因小鼠，该酶合成NMDAR共激动剂D-丝氨酸的酶和SZ的已建立的风险基因，以重建SZ的病理学。通过使用在体内微透析中，通过使用核自刺激和Nucleumbencens中的颅内自刺激和神经递质释放来确定肿瘤嗜酚肌菌产生的影响。与野生型小鼠相比，SR / - 小鼠表现出类似的基线颅内自刺激阈值，但对阈值降低（奖励）和可卡因的性能升高（兴奋剂）效应敏感。虽然在Sr / - 小鼠的核心内升高了基础多巴胺（DA）和谷氨酸释放，但易于诱导的DA和谷氨酸释放的增加的增加。 γ-氨基 - 丁酸流出不受SR / - 小鼠的影响。这些研究结果表明，通过钝化的DA和通常引发的DA和谷氨酸反应介导对Cocaine对可卡因对行为的敏感性的敏感性的敏感性的减少。投射到人类，由于SR中的SR或其他基因突变引起的NMDAR软调可能在SZ中造成抑制物质，因此需要更高的药物，因此需要更高的剂量来实现蜂窝响应，导致升高的药物暴露和增加的依赖性/成瘾。

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