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The Journal of Neuroscience, January 1, 2001, 21(1):305-313
Prepulse Inhibition Deficits and Perseverative Motor Patterns in
Dopamine Transporter Knock-Out Mice: Differential Effects of D1
and D2 Receptor Antagonists
Rebecca J.
Ralph1,
Martin P.
Paulus2,
Fabio
Fumagalli3,
Marc G.
Caron4, and
Mark A.
Geyer2
Departments of 1 Neuroscience and
2 Psychiatry, University of California San Diego, La Jolla,
California 92093-0804, 3 Center of Neuropharmacology,
Institute of Pharmacological Sciences, University of Milan, 20133 Milan, Italy, and 4 Howard Hughes Medical Institute,
Department of Cell Biology, Duke University Medical Center, Durham,
North Carolina 27710
Dopamine is known to regulate several behavioral phenomena,
including sensorimotor gating and aspects of motor activity. The roles
of dopamine D1 and D2 receptors in these behaviors have been documented
in the rat literature, but few reports exist on their role in mice. We
used dopamine transporter (DAT) ( /) mice to examine the behavioral
consequences of a chronically hyperdopaminergic state, challenging them
with the preferential dopamine D2 receptor antagonist raclopride and D1
receptor antagonist SCH23390. At baseline, DAT (/) mice exhibited
deficient sensorimotor gating as measured by prepulse inhibition (PPI)
of the startle response, exhibited nonfocal perseverative patterns of
locomotion, and were hyperactive in a novel environment. Pretreatment
with raclopride significantly increased PPI in the DAT (/) mice,
whereas SCH23390 had no significant effect. Blockade of D2 receptors
did not affect the predominantly straight patterns of motor behavior
produced by the DAT (/) mice, but antagonism of D1 receptors
significantly attenuated the perseverative patterns, producing more of
a meandering behavior seen in the DAT (+/+) control mice. Both D1 and
D2 receptor antagonists decreased the hyperactivity seen in the DAT
(/) mice. These findings support the role of the D2, but not the
D1, receptor in the modulation of PPI in mice. Furthermore, D1 receptor activation appears to be the critical substrate for the expression of
perseverative patterns of motor behavior, whereas both D1 and D2
receptors appear to regulate the amount of motor activity.
Key words:
dopamine; prepulse inhibition; mice; behavior; dopamine
transporter; locomotor activity; perseveration; D1 receptor; D2
receptor
Copyright © 2001 Society for Neuroscience 0270-6474/01/211305-09$05.00/0
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