Cargando…

Enhanced Dopamine Transmission and Hyperactivity in the Dopamine Transporter Heterozygous Mice Lacking the D3 Dopamine Receptor

Dopamine transporter knockout (DATk) mice are known to demonstrate profound hyperactivity concurrent with elevated (5-fold) extracellular dopamine in the basal ganglia. At the same time, heterozygous DAT mice (DATh) demonstrate a 2-fold increase in dopamine levels yet only a marginal elevation in lo...

Descripción completa

Detalles Bibliográficos
Autores principales: Sotnikova, Tatyana D., Efimova, Evgeniya V., Gainetdinov, Raul R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662256/
https://www.ncbi.nlm.nih.gov/pubmed/33153031
http://dx.doi.org/10.3390/ijms21218216
_version_ 1783609357667139584
author Sotnikova, Tatyana D.
Efimova, Evgeniya V.
Gainetdinov, Raul R.
author_facet Sotnikova, Tatyana D.
Efimova, Evgeniya V.
Gainetdinov, Raul R.
author_sort Sotnikova, Tatyana D.
collection PubMed
description Dopamine transporter knockout (DATk) mice are known to demonstrate profound hyperactivity concurrent with elevated (5-fold) extracellular dopamine in the basal ganglia. At the same time, heterozygous DAT mice (DATh) demonstrate a 2-fold increase in dopamine levels yet only a marginal elevation in locomotor activity level. Another model of dopaminergic hyperactivity is the D3 dopamine receptor knockout (D3k) mice, which present only a modest hyperactivity phenotype, predominately manifested as stereotypical behaviors. In the D3k mice, the hyperactivity is also correlated with elevated extracellular dopamine levels (2-fold) in the basal ganglia. Cross-breeding was used to evaluate the functional consequences of the deletion of both genes. In the heterozygous DAT mice, inactivation of the D3R gene (DATh/D3k) resulted in significant hyperactivity and further elevation of striatal extracellular dopamine above levels observed in respective single mutant mice. The decreased weight of DATk mice was evident regardless of the D3 dopamine receptor genotype. In contrast, measures of thermoregulation revealed that the marked hypothermia of DATk mice (−2 °C) was reversed in double knockout mice. Thus, the extracellular dopamine levels elevated by prolonging uptake could be elevated even further by eliminating the D3 receptor. These data also suggest that the hypothermia observed in DATk mice may be mediated through D3 receptors.
format Online
Article
Text
id pubmed-7662256
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-76622562020-11-14 Enhanced Dopamine Transmission and Hyperactivity in the Dopamine Transporter Heterozygous Mice Lacking the D3 Dopamine Receptor Sotnikova, Tatyana D. Efimova, Evgeniya V. Gainetdinov, Raul R. Int J Mol Sci Article Dopamine transporter knockout (DATk) mice are known to demonstrate profound hyperactivity concurrent with elevated (5-fold) extracellular dopamine in the basal ganglia. At the same time, heterozygous DAT mice (DATh) demonstrate a 2-fold increase in dopamine levels yet only a marginal elevation in locomotor activity level. Another model of dopaminergic hyperactivity is the D3 dopamine receptor knockout (D3k) mice, which present only a modest hyperactivity phenotype, predominately manifested as stereotypical behaviors. In the D3k mice, the hyperactivity is also correlated with elevated extracellular dopamine levels (2-fold) in the basal ganglia. Cross-breeding was used to evaluate the functional consequences of the deletion of both genes. In the heterozygous DAT mice, inactivation of the D3R gene (DATh/D3k) resulted in significant hyperactivity and further elevation of striatal extracellular dopamine above levels observed in respective single mutant mice. The decreased weight of DATk mice was evident regardless of the D3 dopamine receptor genotype. In contrast, measures of thermoregulation revealed that the marked hypothermia of DATk mice (−2 °C) was reversed in double knockout mice. Thus, the extracellular dopamine levels elevated by prolonging uptake could be elevated even further by eliminating the D3 receptor. These data also suggest that the hypothermia observed in DATk mice may be mediated through D3 receptors. MDPI 2020-11-03 /pmc/articles/PMC7662256/ /pubmed/33153031 http://dx.doi.org/10.3390/ijms21218216 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sotnikova, Tatyana D.
Efimova, Evgeniya V.
Gainetdinov, Raul R.
Enhanced Dopamine Transmission and Hyperactivity in the Dopamine Transporter Heterozygous Mice Lacking the D3 Dopamine Receptor
title Enhanced Dopamine Transmission and Hyperactivity in the Dopamine Transporter Heterozygous Mice Lacking the D3 Dopamine Receptor
title_full Enhanced Dopamine Transmission and Hyperactivity in the Dopamine Transporter Heterozygous Mice Lacking the D3 Dopamine Receptor
title_fullStr Enhanced Dopamine Transmission and Hyperactivity in the Dopamine Transporter Heterozygous Mice Lacking the D3 Dopamine Receptor
title_full_unstemmed Enhanced Dopamine Transmission and Hyperactivity in the Dopamine Transporter Heterozygous Mice Lacking the D3 Dopamine Receptor
title_short Enhanced Dopamine Transmission and Hyperactivity in the Dopamine Transporter Heterozygous Mice Lacking the D3 Dopamine Receptor
title_sort enhanced dopamine transmission and hyperactivity in the dopamine transporter heterozygous mice lacking the d3 dopamine receptor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662256/
https://www.ncbi.nlm.nih.gov/pubmed/33153031
http://dx.doi.org/10.3390/ijms21218216
work_keys_str_mv AT sotnikovatatyanad enhanceddopaminetransmissionandhyperactivityinthedopaminetransporterheterozygousmicelackingthed3dopaminereceptor
AT efimovaevgeniyav enhanceddopaminetransmissionandhyperactivityinthedopaminetransporterheterozygousmicelackingthed3dopaminereceptor
AT gainetdinovraulr enhanceddopaminetransmissionandhyperactivityinthedopaminetransporterheterozygousmicelackingthed3dopaminereceptor