Reduced expression and capacity of the striatal high-affinity choline transporter in hyperdopaminergic mice.

Full Abstract

Behavioral and neuronal abnormalities observed in mice exhibiting a reduced expression of the dopamine transporter model important aspects of schizophrenia, addiction, and attentional disorders. As the consequences of a chronic hyperdopaminergic tone for striatal output regulation have remained poorly understood, the present experiments were designed to determine the status of striatal interneuronal cholinergic neurotransmission in dopamine transporter knockdown animals. The high-affinity choline transporter represents the rate-limiting step of acetylcholine synthesis and release. Compared with wild type mice, striatal high-affinity choline transporter expression in dopamine transporter knockdown mice was significantly decreased. As in vivo basal striatal acetylcholine release did not differ between the strains, reduced high-affinity choline transporter expression in dopamine transporter knockdown mice was not due to reduced basal cholinergic activity. Furthermore, the proportion of high-affinity choline transporters expressed in plasma membrane-enriched versus vesicular membrane-enriched fractions did not differ from wild type animals, suggesting that changes in intracellular high-affinity choline transporter trafficking were not associated with lower overall levels of striatal high-affinity choline transporters. Synaptosomal choline uptake assays indicated a reduced capacity of striatal high-affinity choline transporters in dopamine transporter knockdown mice, and thus the functional significance of the reduced level of high-affinity choline transporter expression. Likewise, in vivo measures of the capacity of striatal high-affinity choline transporters to clear increases in extracellular choline concentrations, using choline-sensitive microelectrodes, revealed a 37-41% reduction in hemicholinium-sensitive clearance of exogenous choline in dopamine transporter knockdown mice. Furthermore, clearance of potassium-evoked choline signals was reduced in dopamine transporter knockdown mice (1.63+/-0.15 microM/s) compared with wild type animals (2.29+/-0.21 microM/s). Dysregulated striatal cholinergic neurotransmission is hypothesized to disrupt the integration of thalamic and cortical information at spiny projection neurons and thus to contribute to abnormal striatal information processing in dopamine transporter knockdown mice.

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Author information

Author/s: Parikh, V (V); Apparsundaram, S (S); Kozak, R (R); Richards, J B (JB); Sarter, M (M);

Affiliation: Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, MI 48109-1043, USA.

Grants: 5P20RR155592 (Agency:NCRR NIH HHS) ; K02MH01072 (Agency:NIMH NIH HHS) ; R01MH063114 (Agency:NIMH NIH HHS) ; R01NS37026 (Agency:NINDS NIH HHS)

Journal and publication information

Publication Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Neuroscience (Neuroscience), published in United States. (Language: eng)

Reference: 2006-Aug; vol 141 (issue 1) : pp 379-89

Dates: Created 2006/07/03; Completed 2006/09/28; Revised 2007/11/14;

PMID: 16675138, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Acetylcholine - metabolism
Analysis of Variance
Animals
Blotting, Western - methods
Brain Chemistry - genetics
Choline - metabolism; pharmacology
Corpus Striatum - cytology; drug effects; metabolism
Dopamine - metabolism
Dopamine Plasma Membrane Transport Proteins - deficiency

Dose-Response Relationship, Drug
Gene Expression Regulation - genetics; physiology
Hemicholinium 3 - pharmacology
Membrane Transport Proteins - metabolism
Mice
Mice, Knockout
Microdialysis - methods
Neurotransmitter Uptake Inhibitors - pharmacology
Synaptosomes - drug effects; metabolism

Associated Chemicals: Dopamine Plasma Membrane Transport Proteins (0) ; Membrane Transport Proteins (0) ; Neurotransmitter Uptake Inhibitors (0) ; choline transporter (0) ; Hemicholinium 3 (312-45-8) ; Dopamine (51-61-6) ; Acetylcholine (51-84-3) ; Choline (62-49-7)

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