Abstract
Deficits in prepulse inhibition (PPI) of startle, an operational measure of sensorimotor gating, are characteristics of schizophrenia and related neuropsychiatric disorders. Previous studies in mice demonstrate a contribution of dopamine (DA) D1-family receptors in modulating PPI and DA D2 receptors (D2R) in mediating the PPI-disruptive effects of amphetamine. To examine further the contributions of DA receptor subtypes in PPI, we used a combined pharmacological and genetic approach. In congenic C57BL/6 J wild-type mice, we tested whether the D1R antagonist SCH23390 or the D2/3R antagonist raclopride would attenuate the effects of the indirect DA agonist cocaine (40 mg/kg). Both the D1R and D2/3R antagonists attenuated the cocaine-induced PPI deficit. We also tested the effect of cocaine on PPI in wild-type and DA D1R, D2R, or D3R knockout mice. The cocaine-induced PPI deficit was influenced differently by the three DA receptor subtypes, being absent in D1R knockout mice, partially attenuated in D2R knockout mice, and exaggerated in D3R knockout mice. Thus, the D1R is necessary for the PPI-disruptive effects of cocaine, while the D2R partially contributes to these effects. Conversely, the D3R appears to inhibit the PPI-disruptive effects of cocaine. Uncovering neural mechanisms involved in PPI will further our understanding of substrates of sensorimotor gating and could lead to better therapeutics to treat complex cognitive disorders such as schizophrenia.
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Acknowledgements
We thank Mahálah Buell, Sorana Caldwell, and Renee Bend for their technical assistance and Dr Victoria Risbrough for helpful comments on the manuscript.
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DISCLOSURE/CONFLICT OF INTEREST
These studies were supported by NIH MH61326, DA02925 and the Veterans Affairs VISN 22 Mental Illness Research, Education, and Clinical Center. We declare that over the past 3 years MAG has received compensation from Abbott, Acadia, Addex, Amgen, AstraZeneca, Bristol-Myers Squibb, Jazz, Organon, Nura, San Diego Instruments, Serono, and Wyeth-Ayerst and holds an equity interest in San Diego Instruments and MJL has received royalty income and/or stock shares from Amgen, Caliper Life Sciences, Lilly, Orexigen, Pfizer, and Thiakis in compensation for the licensing of intellectual property assigned to OHSU, including the D2R KO mice used in this study.
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Doherty, J., Masten, V., Powell, S. et al. Contributions of Dopamine D1, D2, and D3 Receptor Subtypes to the Disruptive Effects of Cocaine on Prepulse Inhibition in Mice. Neuropsychopharmacol 33, 2648–2656 (2008). https://doi.org/10.1038/sj.npp.1301657
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DOI: https://doi.org/10.1038/sj.npp.1301657
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