Austin J, Buckland P, Cardno A G, Williams N, Spurlock G, Hoogendoorn B, Zammit S, Jones G, Sanders R, Jones L, McCarthy G, Jones S, Bray N J, McGuffin P, Owen M J, O'Donovan M C
Division of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff, UK.
Mol Psychiatry. 2000 Sep;5(5):552-7. doi: 10.1038/sj.mp.4000761.
Neurotensin and its high affinity receptor (NTSR1) localise within dopaminergic neurones in the mesocortical, mesolimbic and nigrostriatal systems and it is now clear that neurotensin can selectively modulate dopaminergic neurotransmission. This has led to the hypothesis that altered neurotensin function contributes to the pathogenesis of schizophrenia and other psychoses. This hypothesis has been supported circumstantially by a number of lines of evidence. (1) Central administration of neurotensin produces effects similar to those produced by the peripheral administration of atypical antipsychotics. (2) Observations of low levels of neurotensin in the CSF of schizophrenics. (3) Reduced numbers of neurotensin receptors in the brains of schizophrenics. Given the above link between neurotensin and dopamine, and the evidence implicating altered neurotensin function in psychosis, we have postulated that DNA sequence variation in neurotensin or its receptors might be associated with schizophrenia. In keeping with this hypothesis, an association has recently been reported between schizophrenia and the gene encoding the neurotensin high affinity receptor (NTSR1). However, caution is required because the associated marker, a tetranucleotide repeat, is located 3 kb away from the 3' end of the gene and there is no evidence that it is functional. Therefore, as a follow-up to our earlier work on neurotensin, we have now sought to test the hypothesis that DNA sequence variants that alter the structure or expression of the NTSR1 gene (VAPSEs) are associated with schizophrenia. However, while we found 14 novel sequence variants in 28 probands with psychosis, none resulted in an amino acid change, and neither direct nor indirect association studies suggested these are involved in susceptibility to schizophrenia.
神经降压素及其高亲和力受体（NTSR1）定位于中皮质、中边缘和黑质纹状体系统的多巴胺能神经元内，现在已经明确神经降压素可以选择性地调节多巴胺能神经传递。这引发了一种假说，即神经降压素功能改变有助于精神分裂症和其他精神病的发病机制。这一假说得到了一系列间接证据的支持。（1）中枢给予神经降压素产生的效应与外周给予非典型抗精神病药物产生的效应相似。（2）观察到精神分裂症患者脑脊液中神经降压素水平较低。（3）精神分裂症患者大脑中神经降压素受体数量减少。鉴于神经降压素与多巴胺之间的上述联系，以及有证据表明神经降压素功能改变与精神病有关，我们推测神经降压素或其受体的DNA序列变异可能与精神分裂症有关。与这一假说一致，最近有报道称精神分裂症与编码神经降压素高亲和力受体（NTSR1）的基因之间存在关联。然而，需要谨慎的是，相关标记物，即四核苷酸重复序列，位于该基因3'端下游3 kb处，且没有证据表明它具有功能。因此，作为我们早期关于神经降压素研究的后续工作，我们现在试图检验这样一种假说，即改变NTSR1基因结构或表达的DNA序列变异（VAPSEs）与精神分裂症有关。然而，虽然我们在28名精神病先证者中发现了14个新的序列变异，但没有一个导致氨基酸改变，直接或间接关联研究均未表明这些变异与精神分裂症易感性有关。
