Selective overexpression of dopamine D3 receptors in the striatum disrupts motivation but not cognition

Eleanor H Simpson; Vanessa Winiger; Dominik K Biezonski; Iram Haq; Eric R Kandel; Christoph Kellendonk

doi:10.1016/j.biopsych.2013.11.023

Selective overexpression of dopamine D3 receptors in the striatum disrupts motivation but not cognition

Biol Psychiatry. 2014 Nov 15;76(10):823-31. doi: 10.1016/j.biopsych.2013.11.023. Epub 2013 Dec 5.

Authors

Eleanor H Simpson¹, Vanessa Winiger², Dominik K Biezonski³, Iram Haq², Eric R Kandel⁴, Christoph Kellendonk⁵

Affiliations

¹ New York State Psychiatric Institute, Columbia University, New York, New York; Department of Psychiatry, Columbia University, New York, New York. Electronic address: es534@columbia.edu.
² Department of Neuroscience, Columbia University, New York, New York.
³ Department of Psychiatry, Columbia University, New York, New York.
⁴ Department of Psychiatry, Columbia University, New York, New York; Department of Neuroscience, Columbia University, New York, New York; Howard Hughes Medical Institute, Chevy Chase, Maryland; The Kavli Institute for Brain Science, Columbia University, New York, New York.
⁵ New York State Psychiatric Institute, Columbia University, New York, New York; Department of Psychiatry, Columbia University, New York, New York; Department of Pharmacology, Columbia University, New York, New York.

Abstract

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.

Keywords: Cognition; dopamine D3 receptor; motivation; schizophrenia; striatum; transgenic model.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anxiety
Cognition / physiology*
Corpus Striatum / metabolism
Corpus Striatum / physiology*
Disease Models, Animal
Down-Regulation
Learning / physiology
Mice
Mice, Transgenic
Motivation / physiology*
Motor Activity
RNA, Messenger / metabolism
Receptors, Dopamine D1 / metabolism
Receptors, Dopamine D3 / genetics
Receptors, Dopamine D3 / metabolism
Receptors, Dopamine D3 / physiology*
Schizophrenia / etiology
Schizophrenia / metabolism*
Sensory Gating / physiology

Substances

RNA, Messenger
Receptors, Dopamine D1
Receptors, Dopamine D3

Abstract

Publication types

MeSH terms

Substances

Grants and funding