Selective overexpression of dopamine D3 receptors in the striatum disrupts motivation but not cognition.
Selective overexpression of dopamine D3 receptors in the striatum disrupts motivation but not cognition.
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DOI：
10.1016/j.biopsych.2013.11.023
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发表时间：
2014-11-15
影响因子：
10.6
通讯作者：
Kellendonk, Christoph
中科院分区：
文献类型：
--
作者：
Simpson, Eleanor H.;Winiger, Vanessa;Biezonski, Dominik K.;Haq, Iram;Kandel, Eric R.;Kellendonk, Christoph
Evidence indicating an increase in dopamine D2 receptor (D2R) density and occupancy in patients with schizophrenia comes from positron emission tomography studies using ligands that bind both D2Rs and dopamine D3 receptors (D3Rs), questioning the role of D3Rs in the pathophysiology of the disease. Dopamine D3 receptor positron emission tomography ligands have recently been developed and antagonists with preferential affinity for D3R versus D2R are undergoing clinical evaluation. To determine if an increase in D3Rs in the striatum could produce phenotypes relevant to schizophrenia, we generated a transgenic model of striatal D3R overexpression. A bi-transgenic system was used to generate mice with increased D3Rs selectively in the striatum. Mice with overexpression of D3R were subjected to an extensive battery of behavioral tests, including several relevant to schizophrenia. Ligand binding and quantitative reverse transcription polymerase chain reaction methods were used to quantify the effect of D3R overexpression on dopamine D1 receptors (D1Rs) in the striatum. Mice with overexpression of D3R show no abnormalities in basic behavioral functions or cognitive tests but do display a deficit in incentive motivation. This was associated with a reduction in striatal D1R ligand binding, driven by a downregulation at the level of transcription. Both motivation and D1R expression were rescued by switching off the transgene in adulthood. Overexpression of D3Rs in the striatum of mice does not elicit cognitive deficits but disrupts motivation, suggesting that changes in D3Rs may be involved in the negative symptoms of schizophrenia. These data imply that it will be important to evaluate the effects of D3R antagonists on motivational symptoms, which are not improved by currently available antipsychotic medications.
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影响因子：
64.8
作者：
Flagel SB;Clark JJ;Robinson TE;Mayo L;Czuj A;Willuhn I;Akers CA;Clinton SM;Phillips PE;Akil H
通讯作者：
Akil H
影响因子：
4.1
作者：
Abi-Dargham, Anissa;Xu, Xiaoyan;Slifstein, Mark
通讯作者：
Slifstein, Mark
影响因子：
5.3
作者：
Napolitano, Francesco;Bonito-Oliva, Alessandra;Usiello, Alessandro
通讯作者：
Usiello, Alessandro
影响因子：
3.2
作者：
KEMALI, D;MAJ, M;MUCCI, A
通讯作者：
MUCCI, A
多巴胺功能障碍在精神分裂症中的性质，这对治疗意味着什么。
影响因子：
--
作者：
Howes, Oliver D.;Kambeitz, Joseph;Kim, Euitae;Stahl, Daniel;Slifstein, Mark;Abi-Dargham, Anissa;Kapur, Shitij
通讯作者：
Kapur, Shitij