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The Journal of Neuroscience, June 1, 1999, 19(11):4627-4633
The Dopamine D2, but not D3 or
D4, Receptor Subtype is Essential for the Disruption of
Prepulse Inhibition Produced by Amphetamine in Mice
Rebecca J.
Ralph1,
Geoffrey B.
Varty2,
Michele
A.
Kelly3,
Yan-Min
Wang5,
Marc G.
Caron5,
Marcelo
Rubinstein6,
David K.
Grandy4,
Malcolm J.
Low3, and
Mark A.
Geyer1, 2
Departments of 1 Neuroscience and
2 Psychiatry, University of California at San Diego, La
Jolla, California 92093-0804, 3 Vollum Institute and
4 Department of Physiology and Pharmacology, Oregon Health
Sciences University, Portland, Oregon 97201, 5 Howard
Hughes Medical Institute Laboratories, Department of Cell Biology, Duke
University Medical Center, Durham North Carolina 27710, and
6 Instituto de Investigaciones en Ingenieriá
Genética y Biología Molecular, Consejo Nacional de
Investigiones Científicas y Técnicas y Departamento de
Biología, Universidad de Buenos Aires, 1428 Buenos Aires,
Argentina
Brain dopamine (DA) systems are involved in the modulation of the
sensorimotor gating phenomenon known as prepulse inhibition (PPI). The
class of D2-like receptors, including the D2, D3, and D4 receptor
subtypes, have all been implicated in the control of PPI via studies of
DA agonists and antagonists in rats. Nevertheless, the functional
relevance of each receptor subtype remains unclear because these
ligands are not specific. To determine the relevance of each receptor
subtype, we used genetically altered strains of "knock-out" mice
lacking the DA D2, D3, or D4 receptors. We tested the effects of each
knock-out on both the phenotypic expression of PPI and the disruption
of PPI produced by the indirect DA agonist d-amphetamine
(AMPH). No phenotypic differences in PPI were observed at baseline.
AMPH significantly disrupted PPI in the D2 (+/+) mice but had no effect
in the D2 ( /) mice. After AMPH treatment, both DA D3 and D4
receptor (+/+) and (/) mice had significant disruptions in PPI.
These findings indicate that the AMPH-induced disruption of PPI is
mediated via the DA D2 receptor and not the D3 or D4 receptor subtypes.
Uncovering the neural mechanisms involved in PPI will further our
understanding of the substrates of sensorimotor gating and could lead
to better therapeutics to treat gating disorders, such as schizophrenia.
Key words:
prepulse inhibition; startle; mice; dopamine receptors; genetics; amphetamine
Copyright © 1999 Society for Neuroscience 0270-6474/99/19114627-07$05.00/0
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