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

Amato D, Canneva F, Cumming P, Maschauer S, Groos D, Dahlmanns JK, Grömer TW, Chiofalo L, Dahlmanns M, Zheng F, Kornhuber J, Prante O, Alzheimer C, von Hörsten S, Müller CP (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Molecular Psychiatry Springer Nature

DOI: 10.1038/s41380-018-0114-5

Abstract

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.

Authors with CRIS profile

Davide Amato Department of Psychiatry and Psychotherapy Simone Maschauer Department of Nuclear Medicine Dominik Groos Lehrstuhl für Physiologie Lisa Chiofalo Medizinische Fakultät Marc Dahlmanns Lehrstuhl für Physiologie Fang Zheng Lehrstuhl für Physiologie Johannes Kornhuber Lehrstuhl für Psychiatrie und Psychotherapie Olaf Prante Professur für Molekulare Bildgebung und Radiochemie Christian Alzheimer Lehrstuhl für Physiologie Stephan von Hörsten Professur für Experimentelle Biomedizin Peter Christian Müller Professur für Suchtmedizin

Involved external institutions

Medical University of South Carolina (MUSC) US United States (USA) (US)

How to cite

APA:

Amato, D., Canneva, F., Cumming, P., Maschauer, S., Groos, D., Dahlmanns, J.K.,... Müller, C.P. (2018). A dopaminergic mechanism of antipsychotic drug efficacy, failure, and failure reversal: the role of the dopamine transporter. Molecular Psychiatry. https://dx.doi.org/10.1038/s41380-018-0114-5

MLA:

Amato, Davide, et al. "A dopaminergic mechanism of antipsychotic drug efficacy, failure, and failure reversal: the role of the dopamine transporter." Molecular Psychiatry (2018).

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