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Adolescent Maturation of Dopamine D1 and D2 Receptor Function and Interactions in Rodents

Adolescence is a developmental period characterized by heightened vulnerability to illicit drug use and the onset of neuropsychiatric disorders. These clinical phenomena likely share common neurobiological substrates, as mesocorticolimbic dopamine systems actively mature during this period. Whereas...

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Autores principales: Dwyer, Jennifer B., Leslie, Frances M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718668/
https://www.ncbi.nlm.nih.gov/pubmed/26784516
http://dx.doi.org/10.1371/journal.pone.0146966
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author Dwyer, Jennifer B.
Leslie, Frances M.
author_facet Dwyer, Jennifer B.
Leslie, Frances M.
author_sort Dwyer, Jennifer B.
collection PubMed
description Adolescence is a developmental period characterized by heightened vulnerability to illicit drug use and the onset of neuropsychiatric disorders. These clinical phenomena likely share common neurobiological substrates, as mesocorticolimbic dopamine systems actively mature during this period. Whereas prior studies have examined age-dependent changes in dopamine receptor binding, there have been fewer functional analyses. The aim of the present study was therefore to determine whether the functional consequences of D1 and D2-like activation are age-dependent. Adolescent and adult rats were given direct D1 and D2 agonists, alone and in combination. Locomotor and stereotypic behaviors were measured, and brains were collected for analysis of mRNA expression for the immediate early genes (IEGs), cfos and arc. Adolescents showed enhanced D2-like receptor control of locomotor and repetitive behaviors, which transitioned to dominant D1-like mechanisms in adulthood. When low doses of agonists were co-administered, adults showed supra-additive behavioral responses to D1/D2 combinations, whereas adolescents did not, which may suggest age differences in D1/D2 synergy. D1/D2-stimulated IEG expression was particularly prominent in the bed nucleus of the stria terminalis (BNST). Given the BNST’s function as an integrator of corticostriatal, hippocampal, and stress-related circuitry, and the importance of neural network dynamics in producing behavior, an exploratory functional network analysis of regional IEG expression was performed. This data-driven analysis demonstrated similar developmental trajectories as those described in humans and suggested that dopaminergic drugs alter forebrain coordinated gene expression age dependently. D1/D2 recruitment of stress nuclei into functional networks was associated with low behavioral output in adolescents. Network analysis presents a novel tool to assess pharmacological action, and highlights critical developmental changes in functional neural circuitry. Immature D1/D2 interactions in adolescents may underlie their unique responses to drugs of abuse and vulnerability to psychopathology. These data highlight the need for age-specific pharmacotherapy design and clinical application in adolescence.
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spelling pubmed-47186682016-01-30 Adolescent Maturation of Dopamine D1 and D2 Receptor Function and Interactions in Rodents Dwyer, Jennifer B. Leslie, Frances M. PLoS One Research Article Adolescence is a developmental period characterized by heightened vulnerability to illicit drug use and the onset of neuropsychiatric disorders. These clinical phenomena likely share common neurobiological substrates, as mesocorticolimbic dopamine systems actively mature during this period. Whereas prior studies have examined age-dependent changes in dopamine receptor binding, there have been fewer functional analyses. The aim of the present study was therefore to determine whether the functional consequences of D1 and D2-like activation are age-dependent. Adolescent and adult rats were given direct D1 and D2 agonists, alone and in combination. Locomotor and stereotypic behaviors were measured, and brains were collected for analysis of mRNA expression for the immediate early genes (IEGs), cfos and arc. Adolescents showed enhanced D2-like receptor control of locomotor and repetitive behaviors, which transitioned to dominant D1-like mechanisms in adulthood. When low doses of agonists were co-administered, adults showed supra-additive behavioral responses to D1/D2 combinations, whereas adolescents did not, which may suggest age differences in D1/D2 synergy. D1/D2-stimulated IEG expression was particularly prominent in the bed nucleus of the stria terminalis (BNST). Given the BNST’s function as an integrator of corticostriatal, hippocampal, and stress-related circuitry, and the importance of neural network dynamics in producing behavior, an exploratory functional network analysis of regional IEG expression was performed. This data-driven analysis demonstrated similar developmental trajectories as those described in humans and suggested that dopaminergic drugs alter forebrain coordinated gene expression age dependently. D1/D2 recruitment of stress nuclei into functional networks was associated with low behavioral output in adolescents. Network analysis presents a novel tool to assess pharmacological action, and highlights critical developmental changes in functional neural circuitry. Immature D1/D2 interactions in adolescents may underlie their unique responses to drugs of abuse and vulnerability to psychopathology. These data highlight the need for age-specific pharmacotherapy design and clinical application in adolescence. Public Library of Science 2016-01-19 /pmc/articles/PMC4718668/ /pubmed/26784516 http://dx.doi.org/10.1371/journal.pone.0146966 Text en © 2016 Dwyer, Leslie http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Dwyer, Jennifer B.
Leslie, Frances M.
Adolescent Maturation of Dopamine D1 and D2 Receptor Function and Interactions in Rodents
title Adolescent Maturation of Dopamine D1 and D2 Receptor Function and Interactions in Rodents
title_full Adolescent Maturation of Dopamine D1 and D2 Receptor Function and Interactions in Rodents
title_fullStr Adolescent Maturation of Dopamine D1 and D2 Receptor Function and Interactions in Rodents
title_full_unstemmed Adolescent Maturation of Dopamine D1 and D2 Receptor Function and Interactions in Rodents
title_short Adolescent Maturation of Dopamine D1 and D2 Receptor Function and Interactions in Rodents
title_sort adolescent maturation of dopamine d1 and d2 receptor function and interactions in rodents
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718668/
https://www.ncbi.nlm.nih.gov/pubmed/26784516
http://dx.doi.org/10.1371/journal.pone.0146966
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