Differential psychostimulant-induced activation of neural circuits in dopamine transporter knockout and wild type mice
Abstract
Dopamine (DA) is a neurotransmitter that has been implicated in a wide variety of psychiatric disorders that include attention deficit-hyperactivity disorder (ADHD), schizophrenia, and drug abuse. Recently, we have been working with a mouse in which the gene for the DA transporter (DAT) has been disrupted. This mouse is hyperactive in the open field, displays an inability to inhibit ongoing behaviors, and is deficient on learning and memory tasks. Psychostimulants such as amphetamine and methylphenidate attenuate the hyperlocomotion of the mutants, but stimulate activity of the wild type (WT) controls. The objective of the present study is to examine the neural basis for the differential responses to psychostimulants in these mice. WT and DAT knockout (KO) animals were given vehicle or methylphenidate, amphetamine, or cocaine and brain sections were immunostained for Fos. In WT mice, methylphenidate induced Fos-like immunoreactivity (Fos-LI) in the mesostriatal and mesolimbocortical DA pathways that included the anterior olfactory nucleus, frontal association cortex, orbitofrontal cortex, cingulate cortex, caudate-putamen, globus pallidus, claustrum, lateral septum, nucleus accumbens, basolateral and central nuclei of the amygdala, bed nucleus of stria terminalis, subthalamic nucleus, substantia nigra, ventral tegmental area, and dorsal raphe. Additional areas of activation included the granular dentate gyrus, Edinger-Westphal nucleus, and periaqueductal gray. While the mutants showed little response in most of these same areas, the anterior olfactory nucleus, caudal caudate-putamen, lateral septum, basolateral and central nuclei of the amygdala, and bed nucleus of stria terminalis were activated. Amphetamine and cocaine produced similar changes to that for methylphenidate, except these psychostimulants also induced Fos-LI in the nucleus accumbens of the KO animals. Since the DAT gene is disrupted in the KO mouse, these findings suggest that dopaminergic mechanisms may mediate the WT responses, whereas non-dopaminergic systems predominate in the mutant. In the mutants, it appears that limbic areas and non-dopaminergic transmitter systems within these brain regions may mediate responses to psychostimulants. Inasmuch as the KO mouse may represent a useful animal model for ADHD and because psychostimulants such as cocaine are reinforcing to these animals, our results may provide some useful insights into the neural mechanisms-other than DA-that may contribute to the symptoms of ADHD and/or drug abuse in human patients.
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DAT knockout mice have been suggested to model ADHD because they are hyperactive, have reduced extinction of responses in food reinforcement operant tasks, and have impaired learning and memory.
“DAT knockout mice have been suggested to model ADHD because they are hyperactive ([443,444]), have reduced extinction of responses in food reinforcement operant tasks [445], and also have impaired learning and memory [444,446].”
From Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings (2012) · cites this paper as [444]
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Self-citation
- Authors
- Trinh, J. V., Nehrenberg, D. L., Jacobsen, J. P. R., Caron, M. G., & Wetsel, W. C.
- Affiliations
- Duke University (US)
- University of North Carolina at Chapel Hill (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Wetsel, W.C
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2003-05
- Volume
- 118
- Issue
- 2
- Pages
- 297-310
- ISSN
- 0306-4522 (ISSN-L)
- OpenAlex
- W2085817655
- Cited by
- 113
- References
- 68
- Citations by year
- 2025: 4 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 3 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 4 · 2015: 4 · 2014: 5 · 2013: 7 · 2012: 5
- FWCI
- 3.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- dopamine transporter knockout mice, psychostimulants, methylphenidate, amphetamine, cocaine, Fos-like immunoreactivity, dopamine, mesostriatal pathway, nucleus accumbens, amygdala, bed nucleus of the stria terminalis, limbic system, attention deficit hyperactivity disorder
- MeSH terms
- Amphetamine, Central Nervous System Stimulants, Animals, Cell Count, Female, Immunohistochemistry, Male, Membrane Glycoproteins, Methylphenidate, Mutation, Nerve Tissue Proteins, Neural Pathways, Time Factors, Blotting, Western, Proto-Oncogene Proteins c-fos, Mice, Knockout, Membrane Transport Proteins, Dopamine Plasma Membrane Transport Proteins, Mice
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