Paternal exposure to methylphenidate induces ADHD-like behavioral phenotypes and altered gene expressions in mouse offspring.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE211982 | GEO | 2023/01/06
REPOSITORIES: GEO
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Project description:Paternal exposure to methylphenidate induces ADHD-like behavioral phenotypes and altered gene expressions in mouse offspring.
| PRJNA873088 | ENA
Project description:To determine whether paternal methamphetamine exposure alters the development, behavior and gene expression of first (F1) and second (F2) generations. We administrated methamphetamine (5 mg/kg) or saline (10 ml/kg) to sire (F0) and performed gene expression profiling analysis using data obtained from RNA-seq of striatum of 7-week-old male F1 mice. Male F1 mice were mated with untreated female mice to obtain F2 mice. Male F1 mice were mated with female mice to obtain F2 mice. RNA-seq of striatum of 7-week-old male F2 mice was also analyzed in the same way.
2024-08-08 | GSE248542 | GEO
Project description:Tissue samples harvested from conventionally-raised sire and their offspring or dysbiotic sire and their offspring were profiled for transcriptome changes using total RNA sequencing. Total RNA was extracted from four different tissue types: sire testis, F1 placenta (at E13.5 & E18.5), and F1 brain and brown adipose tissue (at postnatal day P17).Testis were harvested from 11-weeks inbred male mice that were experiencing gut microbiota dysbiosis for 6-week (antibiotics treated, n=5), or drink sterilized water (control, n=5). While, F1 offspring samples were collected from three independent matings per group and two offspring samples per litter.
2023-11-13 | E-MTAB-10034 | biostudies-arrayexpress
Project description:Background: Methylphenidate (MPH) a psychostimulant prescribed to manage ADHD symptoms, has been increasingly prescribed to children not meeting the strict criteria for ADHD. It has also been misused as a “cognitive enhancer” and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of methylphenidate in mice at either 1mg/kg or 10mg/kg dosing, affects cell number and gene expression in the basal ganglion. Methodology/Principal findings: Through the use of stereological counting methods, we observed a significant reduction (~20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10mg/kg MPH. This dosage of MPH also induced a significant increase in the number of morphologically-activated SNpc microglia. Additionally, exposure to either 1mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopamine neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced oxidative stress. Unbiased gene screening employing Affymetrix GeneChip® HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1mg/kg and 10mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2 and th in the substantia nigra (SN) was observed with both acute and chronic dosing of 10mg/kg MPH. We also found an increase in mRNA levels of the pro-inflammatory genes il-6 and tnf-α in the striatum; although these were seen only at an acute dose of 10mg/kg and not following chronic dosing. Conclusion: Collectively our results suggest that chronic MPH usage in mice, especially at prolonged higher doses, has long-term neurodegenerative consequences.
2012-08-14 | GSE33619 | GEO
Project description:Liver tissue samples were harvested from offspring sired by conventionally-raised male mice or dysbiotic sire, and profiled for genome changes using whole genome sequencing. F1 offspring samples were collected from six independent mating, and gDNA was extracted from offspring liver at postnatal day P17.
2023-11-13 | E-MTAB-10273 | biostudies-arrayexpress
Project description:Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder widely observed from childhood to adulthood, with methylphenidate (MPH) used as the first-line treatment. Recent evidence suggests that the preconception paternal environment can affect offspring health, potentially extending to multiple generations. In our previous study, we reported that MPH administration to sires induced decreased anxiety-related behaviors and memory impairment in the F1 generation. To extend these findings and examine the range of transgenerational effects, this study investigated the impact of preconception male MPH exposure on brain gene expression in the F2 generation.
2025-08-31 | GSE292294 | GEO
Project description:Background: Methylphenidate (MPH) a psychostimulant prescribed to manage ADHD symptoms, has been increasingly prescribed to children not meeting the strict criteria for ADHD. It has also been misused as a “cognitive enhancer” and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of methylphenidate in mice at either 1mg/kg or 10mg/kg dosing, affects cell number and gene expression in the basal ganglion. Methodology/Principal findings: Through the use of stereological counting methods, we observed a significant reduction (~20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10mg/kg MPH. This dosage of MPH also induced a significant increase in the number of morphologically-activated SNpc microglia. Additionally, exposure to either 1mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopamine neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced oxidative stress. Unbiased gene screening employing Affymetrix GeneChip® HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1mg/kg and 10mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2 and th in the substantia nigra (SN) was observed with both acute and chronic dosing of 10mg/kg MPH. We also found an increase in mRNA levels of the pro-inflammatory genes il-6 and tnf-α in the striatum; although these were seen only at an acute dose of 10mg/kg and not following chronic dosing. Conclusion: Collectively our results suggest that chronic MPH usage in mice, especially at prolonged higher doses, has long-term neurodegenerative consequences. drug treatment: 3 control, 3 low dose treatment, 3 high dose treatment
2012-08-13 | E-GEOD-33619 | biostudies-arrayexpress
Project description:Preclinical studies suggest that parental exposure to drugs of abuse such as opioids can have profound and long-lasting effects on reward processing and drug sensitivity across generations. However, little is known about the impact of long-term paternal morphine exposure on sensitivity to morphine-derived antinociception in offspring. We developed a novel sub-second pain scale with statistical modeling and machine learning to measure mechanical nociception in Long Evans and Sprague Dawley male and female rats. Next, we used this rat pain scale with a multigenerational paternal morphine exposure paradigm to determine whether chronic paternal morphine exposure impacts pain sensitivity in offspring. Finally, we used RNA sequencing to identify potential molecular correlates of sire exposure to morphine on offspring. Surprisingly, we found that von Frey hair filaments (VFHs), the most commonly-used noxious mechanical stimuli to test pain sensitivity, are not painful to rats as measured by this novel rat pain scale. Male progeny produced from morphine-treated sires did not exhibit any baseline changes in sensitivity to noxious mechanical stimuli but had greater sensitivity to the antinociceptive properties of morphine. Changes in gene expression within the periaqueductal gray, including primary members of the RGS family of proteins, were identified that may play a role in modified sensitivity to morphine within offspring. These findings reveal nuanced responses to VFHs that should be considered in future pain studies and demonstrate that long-term paternal exposure to morphine increases sensitivity to morphine-derived analgesia in the subsequent male generation.
2025-05-20 | GSE174846 | GEO
Project description:Stimulant medication has long been effective in treating attention-deficit/hyperactivity disorder (ADHD) and is currently the first-line pharmacological treatment for children. Both methylphenidate and amphetamine modulate extracellular catecholamine levels through interaction with dopaminergic, adrenergic and serotonergic system components; it is therefore likely that catecholaminergic molecular components influence the effects of ADHD treatment. Using meta-analysis, we sought to identify predictors of pharmacotherapy to further the clinical implementation of personalized medicine. We identified 36 studies (3647 children) linking the effectiveness of methylphenidate treatment with DNA variants. Pooled-data revealed a statistically significant association between single nucleotide polymorphisms (SNPs) rs1800544 ADRA2A (odds ratio: 1.69; confidence interval: 1.12-2.55), rs4680 COMT (odds ratio (OR): 1.40; confidence interval: 1.04-1.87), rs5569 SLC6A2 (odds ratio: 1.73; confidence interval: 1.26-2.37) and rs28386840 SLC6A2 (odds ratio: 2.93; confidence interval: 1.76-4.90), and, repeat variants variable number tandem repeat (VNTR) 4 DRD4 (odds ratio: 1.66; confidence interval: 1.16-2.37) and VNTR 10 SLC6A3 (odds ratio: 0.74; confidence interval: 0.60-0.90), whereas the following variants were not statistically significant: rs1947274 LPHN3 (odds ratio: 0.95; confidence interval: 0.71-1.26), rs5661665 LPHN3 (odds ratio: 1.07; confidence interval: 0.84-1.37) and VNTR 7 DRD4 (odds ratio: 0.68; confidence interval: 0.47-1.00). Funnel plot asymmetry among SLC6A3 studies was identified and attributed largely to small study effects. Egger's regression test and Duval and Tweedie's 'trim and fill' were used to examine and correct for publication bias. These findings have major implications for advancing our therapeutic approach to childhood ADHD treatment.
| S-EPMC7039663 | biostudies-literature
Project description:Animal models of ADHD suggest that the paradoxical calming effect of methylphenidate on motor activity could be mediated through its action on serotonin transmission. In this study, we have investigated the relationship between the 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4) and the response of ADHD relevant behaviors with methylphenidate treatment.Patients between ages 6-12 (n = 157) were assessed with regard to their behavioral response to methylphenidate (0.5 mg/kg/day) using a 2-week prospective within-subject, placebo-controlled (crossover) trial. The children were then genotyped with regard to the triallelic 5-HTTLPR polymorphism in the SLC6A4 gene.Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) at baseline and at the end of each week of treatment with placebo and methylphenidate. For both outcome measurements, we used a mixed model analysis of variance to determine gene, treatment and gene x treatment interaction effects.Mixed model analysis of variance revealed a gene x treatment interaction for CGI-Parents but not for CGI-Teachers. Children homozygous for the lower expressing alleles (s+lG = s') responded well to placebo and did not derive additional improvement with methylphenidate compared to children carrying a higher expressing allele (lA). No genotype main effects on either CGI-Parents or CGI-teachers were observed.A double blind placebo-controlled design was used to assess the behavioral effects of methylphenidate in relation to the triallelic 5-HTTLPR polymorphism of the SLC6A4 gene in children with ADHD. This polymorphism appears to modulate the behavioral response to methylphenidate in children with ADHD as assessed in the home environment by parents. Further investigation is needed to assess the clinical implications of this finding.ClinicalTrials.gov NCT00483106.
| S-EPMC2905344 | biostudies-literature