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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)

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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)

Ike dela Peña et al. Behav Brain Funct.

Abstract

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.

Figures

Figure 1
Figure 1
Reinforcing effects of repeated methylphenidate treatment in spontaneously hypertensive rats (SHRs). (A) Methylphenidate (MPH) CPP in cohort 1 (saline-pretreated SHR conditioned with methylphenidate, SAL + MPH) and cohort 2 (methylphenidate-pretreated SHR conditioned methylphenidate, MPH + MPH) rats. During the conditioning phase of the CPP test, the rats in both cohorts were administered 5 mg/kg dose of MPH. The control group received saline only. Each bar represents the mean ± S.E.M. of the difference in the time spent in the drug- or saline- (for control group) paired side during the post- and preconditioning phases. ***P < 0.001, significantly different from the saline-treated groups. n = 10-12 rats per group. (B) MPH self-administration shown by saline-treated (SAL + MPH) and methylphenidate-pretreated (MPH + MPH) SHR. The mean number of methylphenidate infusions obtained by rats over the 6 days of methylphenidate self-administration is shown. Each symbol represents the mean ± S.E.M. n = 7-9 animals per group.
Figure 2
Figure 2
The confirmed changes in the prefrontal cortical and striatal gene expression in cohort 2 spontaneously hypertensive rats (SHRs). qRT-PCR validated the expression of Homer1, S100a9 and Angptl4, differentially expressed genes (DEGs) in the prefrontal cortex (PFC), as well as Pcdh10, Ctnnd1, Uqcrc2, Nedd4, and Perp, DEGs in the striatum of cohort 2 SHRs. The data represent the expression ratios with respect to the control group (Con), and the values were normalized to GAPDH. *P < 0.05, **P < 0.01 significantly different from the control groups.

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