A dopaminergic mechanism of antipsychotic drug efficacy, failure, and failure reversal: the role of the dopamine transporter

被引：53

作者：

Amato, Davide ^{[1
,2
]}

Canneva, Fabio ^{[3
]}

Cumming, Paul ^{[4
,5
,6
,7
]}

Maschauer, Simone ^{[4
]}

Groos, Dominik ^{[8
]}

Dahlmanns, Jana Katharina ^{[2
]}

Groemer, Teja W. ^{[1
]}

Chiofalo, Lisa ^{[1
]}

Dahlmanns, Marc ^{[1
]}

Zheng, Fang ^{[8
]}

Kornhuber, Johannes ^{[1
]}

Prante, Olaf ^{[4
]}

Alzheimer, Christian ^{[8
]}

von Hoersten, Stephan ^{[3
]}

Mueller, Christian P. ^{[1
]}

机构：

[1] Friedrich Alexander Univ Erlangen Nurnberg, Univ Clin, Dept Psychiat & Psychotherapy, Erlangen, Germany

[2] Med Univ South Carolina, Dept Neurosci, Charleston, SC 29425 USA

[3] Friedrich Alexander Univ Erlangen Nurnberg, Preclin Expt Ctr, Dept Expt Therapy, Erlangen, Germany

[4] Friedrich Alexander Univ Erlangen Nurnberg, Dept Nucl Med Mol Imaging & Radiochem, Erlangen, Germany

[5] Queensland Univ Technol, Sch Psychol & Counselling, Brisbane, Qld, Australia

[6] Queensland Univ Technol, IHBI, Brisbane, Qld, Australia

[7] QIMR Berghofer Med Res Inst, Brisbane, Qld, Australia

[8] Friedrich Alexander Univ Erlangen Nurnberg, Inst Physiol & Pathophysiol, Erlangen, Germany

来源：

MOLECULAR PSYCHIATRY | 2020年 / 25卷 / 09期

关键词：

SUBSTANTIA-NIGRA NEURONS; CLINICAL-RESPONSE; RAT STRIATUM; IN-VIVO; SUPERSENSITIVITY PSYCHOSIS; CHRONIC-SCHIZOPHRENIA; CHRONIC HALOPERIDOL; RECEPTOR BLOCKADE; D2; RECEPTOR; RELEASE;

D O I：

10.1038/s41380-018-0114-5

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Antipsychotic drugs are effective interventions in schizophrenia. However, the efficacy of these agents often decreases over time, which leads to treatment failure and symptom recurrence. We report that antipsychotic efficacy in rat models declines in concert with extracellular striatal dopamine levels rather than insufficient dopamine D2 receptor occupancy. Antipsychotic efficacy was associated with a suppression of dopamine transporter activity, which was reversed during failure. Antipsychotic failure coincided with reduced dopamine neuron firing, which was not observed during antipsychotic efficacy. Synaptic field responses in dopamine target areas declined during antipsychotic efficacy and showed potentiation during failure. Antipsychotics blocked synaptic vesicle release during efficacy but enhanced this release during failure. We found that the pharmacological inhibition of the dopamine transporter rescued antipsychotic drug treatment outcomes, supporting the hypothesis that the dopamine transporter is a main target of antipsychotic drugs and predicting that dopamine transporter blockers may be an adjunct treatment to reverse antipsychotic treatment failure.

引用

页码：2101 / 2118

页数：18

共 76 条

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