Cargando…
Prefrontal cortical and striatal transcriptional responses to the reinforcing effect of repeated methylphenidate treatment in the spontaneously hypertensive rat, animal model of attention-deficit/hyperactivity disorder (ADHD)
BACKGROUND: Methylphenidate is the most commonly used stimulant drug for the treatment of attention-deficit/hyperactivity disorder (ADHD). Research has found that methylphenidate is a “reinforcer” and that individuals with ADHD also abuse this medication. Nevertheless, the molecular consequences of...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077266/ https://www.ncbi.nlm.nih.gov/pubmed/24884696 http://dx.doi.org/10.1186/1744-9081-10-17 |
_version_ | 1782323580235677696 |
---|---|
author | dela Peña, Ike Kim, Hee Jin Sohn, Aeree Kim, Bung-Nyun Han, Doug Hyun Ryu, Jong Hoon Shin, Chan Young Noh, Minsoo Cheong, Jae Hoon |
author_facet | dela Peña, Ike Kim, Hee Jin Sohn, Aeree Kim, Bung-Nyun Han, Doug Hyun Ryu, Jong Hoon Shin, Chan Young Noh, Minsoo Cheong, Jae Hoon |
author_sort | dela Peña, Ike |
collection | PubMed |
description | BACKGROUND: Methylphenidate is the most commonly used stimulant drug for the treatment of attention-deficit/hyperactivity disorder (ADHD). Research has found that methylphenidate is a “reinforcer” and that individuals with ADHD also abuse this medication. Nevertheless, the molecular consequences of long-term recreational methylphenidate use or abuse in individuals with ADHD are not yet fully known. METHODS: Spontaneously hypertensive rats (SHR), the most validated and widely used ADHD animal model, were pretreated with methylphenidate (5 mg/kg, i.p.) during their adolescence (post-natal day [PND] 42–48) and tested for subsequent methylphenidate-induced conditioned place preference (CPP) and self-administration. Thereafter, the differentially expressed genes in the prefrontal cortex (PFC) and striatum of representative methylphenidate-treated SHRs, which showed CPP to and self-administration of methylphenidate, were analyzed. RESULTS: Genome-wide transcriptome profiling analyses revealed 30 differentially expressed genes in the PFC, which include transcripts involved in apoptosis (e.g. S100a9, Angptl4, Nfkbia), transcription (Cebpb, Per3), and neuronal plasticity (Homer1, Jam2, Asap1). In contrast, 306 genes were differentially expressed in the striatum and among them, 252 were downregulated. The main functional categories overrepresented among the downregulated genes include those involved in cell adhesion (e.g. Pcdh10, Ctbbd1, Itgb6), positive regulation of apoptosis (Perp, Taf1, Api5), (Notch3, Nsbp1, Sik1), mitochondrion organization (Prps18c, Letm1, Uqcrc2), and ubiquitin-mediated proteolysis (Nedd4, Usp27x, Ube2d2). CONCLUSION: Together, these changes indicate methylphenidate-induced neurotoxicity, altered synaptic and neuronal plasticity, energy metabolism and ubiquitin-dependent protein degradation in the brains of methylphenidate-treated SHRs, which showed methylphenidate CPP and self-administration. In addition, these findings may also reflect cognitive impairment associated with chronic methylphenidate use as demonstrated in preclinical studies. Future studies are warranted to determine the clinical significance of the present findings with regard to long-term recreational methylphenidate use or abuse in individuals with ADHD. |
format | Online Article Text |
id | pubmed-4077266 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-40772662014-07-02 Prefrontal cortical and striatal transcriptional responses to the reinforcing effect of repeated methylphenidate treatment in the spontaneously hypertensive rat, animal model of attention-deficit/hyperactivity disorder (ADHD) dela Peña, Ike Kim, Hee Jin Sohn, Aeree Kim, Bung-Nyun Han, Doug Hyun Ryu, Jong Hoon Shin, Chan Young Noh, Minsoo Cheong, Jae Hoon Behav Brain Funct Research BACKGROUND: Methylphenidate is the most commonly used stimulant drug for the treatment of attention-deficit/hyperactivity disorder (ADHD). Research has found that methylphenidate is a “reinforcer” and that individuals with ADHD also abuse this medication. Nevertheless, the molecular consequences of long-term recreational methylphenidate use or abuse in individuals with ADHD are not yet fully known. METHODS: Spontaneously hypertensive rats (SHR), the most validated and widely used ADHD animal model, were pretreated with methylphenidate (5 mg/kg, i.p.) during their adolescence (post-natal day [PND] 42–48) and tested for subsequent methylphenidate-induced conditioned place preference (CPP) and self-administration. Thereafter, the differentially expressed genes in the prefrontal cortex (PFC) and striatum of representative methylphenidate-treated SHRs, which showed CPP to and self-administration of methylphenidate, were analyzed. RESULTS: Genome-wide transcriptome profiling analyses revealed 30 differentially expressed genes in the PFC, which include transcripts involved in apoptosis (e.g. S100a9, Angptl4, Nfkbia), transcription (Cebpb, Per3), and neuronal plasticity (Homer1, Jam2, Asap1). In contrast, 306 genes were differentially expressed in the striatum and among them, 252 were downregulated. The main functional categories overrepresented among the downregulated genes include those involved in cell adhesion (e.g. Pcdh10, Ctbbd1, Itgb6), positive regulation of apoptosis (Perp, Taf1, Api5), (Notch3, Nsbp1, Sik1), mitochondrion organization (Prps18c, Letm1, Uqcrc2), and ubiquitin-mediated proteolysis (Nedd4, Usp27x, Ube2d2). CONCLUSION: Together, these changes indicate methylphenidate-induced neurotoxicity, altered synaptic and neuronal plasticity, energy metabolism and ubiquitin-dependent protein degradation in the brains of methylphenidate-treated SHRs, which showed methylphenidate CPP and self-administration. In addition, these findings may also reflect cognitive impairment associated with chronic methylphenidate use as demonstrated in preclinical studies. Future studies are warranted to determine the clinical significance of the present findings with regard to long-term recreational methylphenidate use or abuse in individuals with ADHD. BioMed Central 2014-05-06 /pmc/articles/PMC4077266/ /pubmed/24884696 http://dx.doi.org/10.1186/1744-9081-10-17 Text en Copyright © 2014 dela Peña et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research dela Peña, Ike Kim, Hee Jin Sohn, Aeree Kim, Bung-Nyun Han, Doug Hyun Ryu, Jong Hoon Shin, Chan Young Noh, Minsoo Cheong, Jae Hoon Prefrontal cortical and striatal transcriptional responses to the reinforcing effect of repeated methylphenidate treatment in the spontaneously hypertensive rat, animal model of attention-deficit/hyperactivity disorder (ADHD) |
title | Prefrontal cortical and striatal transcriptional responses to the reinforcing effect of repeated methylphenidate treatment in the spontaneously hypertensive rat, animal model of attention-deficit/hyperactivity disorder (ADHD) |
title_full | Prefrontal cortical and striatal transcriptional responses to the reinforcing effect of repeated methylphenidate treatment in the spontaneously hypertensive rat, animal model of attention-deficit/hyperactivity disorder (ADHD) |
title_fullStr | Prefrontal cortical and striatal transcriptional responses to the reinforcing effect of repeated methylphenidate treatment in the spontaneously hypertensive rat, animal model of attention-deficit/hyperactivity disorder (ADHD) |
title_full_unstemmed | Prefrontal cortical and striatal transcriptional responses to the reinforcing effect of repeated methylphenidate treatment in the spontaneously hypertensive rat, animal model of attention-deficit/hyperactivity disorder (ADHD) |
title_short | Prefrontal cortical and striatal transcriptional responses to the reinforcing effect of repeated methylphenidate treatment in the spontaneously hypertensive rat, animal model of attention-deficit/hyperactivity disorder (ADHD) |
title_sort | prefrontal cortical and striatal transcriptional responses to the reinforcing effect of repeated methylphenidate treatment in the spontaneously hypertensive rat, animal model of attention-deficit/hyperactivity disorder (adhd) |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077266/ https://www.ncbi.nlm.nih.gov/pubmed/24884696 http://dx.doi.org/10.1186/1744-9081-10-17 |
work_keys_str_mv | AT delapenaike prefrontalcorticalandstriataltranscriptionalresponsestothereinforcingeffectofrepeatedmethylphenidatetreatmentinthespontaneouslyhypertensiveratanimalmodelofattentiondeficithyperactivitydisorderadhd AT kimheejin prefrontalcorticalandstriataltranscriptionalresponsestothereinforcingeffectofrepeatedmethylphenidatetreatmentinthespontaneouslyhypertensiveratanimalmodelofattentiondeficithyperactivitydisorderadhd AT sohnaeree prefrontalcorticalandstriataltranscriptionalresponsestothereinforcingeffectofrepeatedmethylphenidatetreatmentinthespontaneouslyhypertensiveratanimalmodelofattentiondeficithyperactivitydisorderadhd AT kimbungnyun prefrontalcorticalandstriataltranscriptionalresponsestothereinforcingeffectofrepeatedmethylphenidatetreatmentinthespontaneouslyhypertensiveratanimalmodelofattentiondeficithyperactivitydisorderadhd AT handoughyun prefrontalcorticalandstriataltranscriptionalresponsestothereinforcingeffectofrepeatedmethylphenidatetreatmentinthespontaneouslyhypertensiveratanimalmodelofattentiondeficithyperactivitydisorderadhd AT ryujonghoon prefrontalcorticalandstriataltranscriptionalresponsestothereinforcingeffectofrepeatedmethylphenidatetreatmentinthespontaneouslyhypertensiveratanimalmodelofattentiondeficithyperactivitydisorderadhd AT shinchanyoung prefrontalcorticalandstriataltranscriptionalresponsestothereinforcingeffectofrepeatedmethylphenidatetreatmentinthespontaneouslyhypertensiveratanimalmodelofattentiondeficithyperactivitydisorderadhd AT nohminsoo prefrontalcorticalandstriataltranscriptionalresponsestothereinforcingeffectofrepeatedmethylphenidatetreatmentinthespontaneouslyhypertensiveratanimalmodelofattentiondeficithyperactivitydisorderadhd AT cheongjaehoon prefrontalcorticalandstriataltranscriptionalresponsestothereinforcingeffectofrepeatedmethylphenidatetreatmentinthespontaneouslyhypertensiveratanimalmodelofattentiondeficithyperactivitydisorderadhd |