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Prepulse Inhibition Deficits and Perseverative Motor Patterns in Dopamine Transporter Knock-Out Mice: Differential Effects of D1 and D2 Receptor Antagonists
Open accessAbstract
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.
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“The DAT knockout mice phenotypes resemble amphetamine-like effects, and both hyperlocomotion and PPI deficits can be reversed with either D1 or D2 receptor antagonists [376], the atypical antipsychotics clozapine and quetiapine [377], various antidepressant drugs, and monoamine transporter inhibitors [378].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [376]
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“Mice lacking the DAT gene display markedly increased levels of DA in the mesolimbic system and striatum [373], that results in hyperlocomoter behaviors [373,374] and also deficits in PPI [375,376].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [376]
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Metadata
- Authors
- Ralph, R. J., Paulus, M. P., Fumagalli, F., Caron, M. G., & Geyer, M. A.
- Affiliations
- University of California San Diego (US)
- University of Milan (IT)
- Howard Hughes Medical Institute (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2001-01-01
- Volume
- 21
- Issue
- 1
- Pages
- 305-313
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6762423
- OpenAlex
- W2133067994
- Cited by
- 271
- References
- 31
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 4 · 2023: 12 · 2022: 9 · 2021: 4 · 2020: 7 · 2019: 7 · 2018: 6 · 2017: 8 · 2016: 13 · 2015: 12 · 2014: 15 · 2013: 12 · 2012: 11
- FWCI
- 5.16
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Veterans Affairs
- National Institutes of Health (5r01da011277-03)
- National Institute of Mental Health (F31-MH-12806, MH42228, R37MH042228, R01MH042228, R01MH061326)
- National Institute on Drug Abuse (DA 02925, R01DA002925, DA11277)
- NIH Clinical Center
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- prepulse inhibition, sensorimotor gating, dopamine transporter knockout mice, dopamine D1 receptor, dopamine D2 receptor, dopamine D1 receptor antagonist, dopamine D2 receptor antagonists, raclopride, SCH 23390, locomotor hyperactivity, hyperdopaminergic state
- MeSH terms
- Animals, Behavior, Animal, Benzazepines, Carrier Proteins, Female, Heterozygote, Homozygote, Hyperkinesis, Injections, Intraperitoneal, Injections, Subcutaneous, Male, Membrane Glycoproteins, Motor Activity, Movement Disorders, Nerve Tissue Proteins, Neural Inhibition, Sex Factors, Reflex, Startle, Receptors, Dopamine D1, Receptors, Dopamine D2, Mice, Knockout, Dopamine Antagonists, Raclopride, Membrane Transport Proteins, Dopamine Plasma Membrane Transport Proteins, Mice, Dopamine D2 Receptor Antagonists
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