Imperial College London
Professor Dominic Withers

ProfessorDominicWithers

Faculty of Medicine, Institute of Clinical Sciences

Clinical Chair in Diabetes & Endocrinology
 
 
 
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Contact

 

d.withers

 
 
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Location

 

Hammersmith HospitalHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Kokkinou:2020:10.1038/s41380-020-0740-6,
author = {Kokkinou, M and Irvine, EE and Bonsall, DR and Natesan, S and Wells, LA and Smith, M and Glegola, J and Paul, EJ and Tossell, K and Veronese, M and Khadayate, S and Dedic, N and Hopkins, SC and Ungless, MA and Withers, DJ and Howes, OD},
doi = {10.1038/s41380-020-0740-6},
journal = {Molecular Psychiatry},
pages = {2562--2576},
title = {Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine},
url = {http://dx.doi.org/10.1038/s41380-020-0740-6},
volume = {26},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Patients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. The mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we develop a translational mouse model of the dopamine pathophysiology seen in schizophrenia and test approaches to reverse the dopamine changes. Mice were treated with sub-chronic ketamine (30 mg/kg) or saline and then received in vivo positron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open-field test. In vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohen’s d = 2.5) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of PV interneurons in pre-limbic cortex and ventral subiculum of the hippocampus. Sub-chronic ketamine reduced PV expression in these cortical and hippocampal regions. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1) and 5-HT1A receptors but no appreciable action at dopamine D2 receptors, significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, that this requires activation of midbrain dopamine neurons, and can be ameliorated by activating PV interneurons and by a TAAR1/5-HT1A agonist. This identifies novel therapeutic approaches for targeting presynaptic dopamine dysfunction in patients with schiz
AU  - Kokkinou,M
AU  - Irvine,EE
AU  - Bonsall,DR
AU  - Natesan,S
AU  - Wells,LA
AU  - Smith,M
AU  - Glegola,J
AU  - Paul,EJ
AU  - Tossell,K
AU  - Veronese,M
AU  - Khadayate,S
AU  - Dedic,N
AU  - Hopkins,SC
AU  - Ungless,MA
AU  - Withers,DJ
AU  - Howes,OD
DO  - 10.1038/s41380-020-0740-6
EP  - 2576
PY  - 2020///
SN  - 1359-4184
SP  - 2562
TI  - Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine
T2  - Molecular Psychiatry
UR  - http://dx.doi.org/10.1038/s41380-020-0740-6
UR  - https://www.nature.com/articles/s41380-020-0740-6
UR  - http://hdl.handle.net/10044/1/79184
VL  - 26
ER  -
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