Dysregulated 5-HT(2A) receptor binding in postmortem frontal cortex of schizophrenic subjects.
Dysregulated 5-HT(2A) receptor binding in postmortem frontal cortex of schizophrenic subjects.
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DOI：
10.1016/j.euroneuro.2012.10.006
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发表时间：
2013-08
影响因子：
5.6
通讯作者：
Gonzalez-Maeso, Javier
中科院分区：
文献类型：
--
作者：
Muguruza, Carolina;Moreno, Jose L.;Umali, Adrienne;Callado, Luis F.;Javier Meana, J.;Gonzalez-Maeso, Javier
关键词：
先前的尸检和神经影像学研究一再表明，5-羟色胺5-HT 2A受体（5-HT 2AR）结合的改变与精神分裂症的病理生理学相关。这些研究是用配体如酮色林、阿坦色林和LSD进行的，这些配体可以高亲和力结合5-HT 2AR的不同结构或功能构象。结果的解释也可能被精神分裂症组的慢性抗精神病药物治疗和自杀行为混淆。我们定量5-HT 2AR密度的放射性配体结合分析，在死后的前额叶皮质抗精神病药物免费（n=29）和抗精神病药物治疗（n=16）精神分裂症，自杀的受害者与其他精神病诊断（n=13），和单独匹配的控制。测定了[3 H]酮色林结合及其被阿坦色林或LSD样激动剂DOI置换。结果表明，[3 H]酮色林与5-HT 2AR结合位点的数量在无抗精神病药物的精神分裂症受试者中增加（128±11%），但在抗精神病药物治疗的精神分裂症受试者中没有增加（92±12%）。在自杀受害者中，与对照组相比，[3 H]酮色林结合没有差异。在精神分裂症、自杀受害者和对照组中，衰老与[3 H]酮色林结合呈负相关。DOI置换[3 H]酮色林结合5-HT 2AR的高亲和力位点的分数在无抗精神病药物的精神分裂症受试者中增加。异源三聚体G蛋白的功能解偶联导致阿坦色林取代[3 H]酮色林结合到精神分裂症受试者的5-HT 2AR的高亲和力位点的分数增加，但在对照组中没有。总之，这些结果表明，5-HT 2AR的活性构象上调抗精神病药物自由精神分裂症受试者的前额叶皮层，并可能提供一个药理学解释先前获得的不一致的结果。
Previous postmortem and neuroimaging studies have repeatedly suggested alterations in serotonin 5-HT2A receptor (5-HT2AR) binding associated with the pathophysiology of schizophrenia. These studies were performed with ligands, such as ketanserin, altanserin and LSD, that may bind with high-affinity to different structural or functional conformations of the 5-HT2AR. Interpretation of results may also be confounded by chronic antipsychotic treatment and suicidal behavior in the schizophrenia group. We quantified 5-HT2AR density by radioligand binding assays in postmortem prefrontal cortex of antipsychotic-free (n=29) and antipsychotic-treated (n=16) schizophrenics, suicide victims with other psychiatric diagnoses (n=13), and individually matched controls. [3H]Ketanserin binding, and its displacement by altanserin or the LSD-like agonist DOI, was assayed. Results indicate that the number of [3H]ketanserin binding sites to the 5-HT2AR was increased in antipsychotic-free (128±11%), but not in antipsychotic-treated (92±12%), schizophrenic subjects. In suicide victims, [3H]ketanserin binding did not differ as compared to controls. Aging correlated negatively with [3H]ketanserin binding in schizophrenia, suicide victims and controls. The fraction of high-affinity sites of DOI displacing [3H]ketanserin binding to the 5-HT2AR was increased in antipsychotic-free schizophrenic subjects. Functional uncoupling of heterotrimeric G proteins led to increased fraction of high-affinity sites of altanserin displacing [3H]ketanserin binding to the 5-HT2AR in schizophrenic subjects, but not in controls. Together, these results suggest that the active conformation of the 5-HT2AR is up-regulated in prefrontal cortex of antipsychotic-free schizophrenic subjects, and may provide a pharmacological explanation for discordant findings previously obtained.
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DOI：
10.1192/bjp.108.452.95
发表时间：
1962-01-01
期刊：
JOURNAL OF MENTAL SCIENCE
影响因子：
--
作者：
ANASTASOPOULOS, G;PHOTIADE.H
通讯作者：
PHOTIADE.H
影响因子：
10.6
作者：
Gurevich, EV;Joyce, JN
通讯作者：
Joyce, JN
影响因子：
4.5
作者：
Dean, Brian;Crossland, Nicola;Scarr, Elizabeth
通讯作者：
Scarr, Elizabeth
影响因子：
2.9
作者：
GROSSISSEROFF, R;SALAMA, D;BIEGON, A
通讯作者：
BIEGON, A
影响因子：
7.6
作者：
JOYCE, JN;SHANE, A;KLEINMAN, JE
通讯作者：
KLEINMAN, JE