Background
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.
Methods
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.
Results
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.
Conclusions
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.
Key Words
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Article Info
Publication History
Published online: December 06, 2013
Accepted:
November 18,
2013
Received in revised form:
November 1,
2013
Received:
February 6,
2013
Identification
Copyright
© 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
