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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

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Copyright © 2001 Society for Neuroscience  0270-6474/01/211305-09$05.00/0

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