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

Davide Amato,Paul Cumming,Olaf Prante,Teja W Grömer,Simone Maschauer,Christian Alzheimer,Fabio Canneva,Stephan Von Hörsten,Marc Dahlmanns,Dominik Groos,Christian P Müller,Fang Zheng,Johannes Kornhuber,Lisa Chiofalo,Jana Katharina Dahlmanns

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.

Highlights

Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Antipsychotic drugs (APDs) are a mainstay in the treatment of schizophrenia
The occurrence of relapse during APD treatment of schizophrenia is attributed to an excessive potentiation of dopaminergic neurotransmission [25,26,27,28]
We found that ~69% of striatal D2 receptors were occupied by HAL (Fig. 2a), which indicates that the loss of HAL efficacy observed in the behavioral tests might occur despite constant and significant D2 receptor occupancy by HAL

Summary

Introduction

Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) studies define the incremental lack of antipsychotic efficacy as one of the main factors of drug discontinuation, which was observed within 18 months after treatment initiation in 75% of patients [6,7,8]. Related to this acquired pharmacological resistance, ~20% of all schizophrenia patients will never respond to APDs, even if a consistent D2 receptor occupancy is maintained at the start of the treatment within the therapeutic window [9,10,11]. To understand the neurobiology of APDs efficacy and failure, we probed the underlying neurochemical and neurophysiological mechanisms and developed a rational pharmacological intervention to ameliorate the loss of APD effects

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Conclusion