The disruptive effects of methylphenidate treatment on circadian rhythm in adult female zebrafish and epigenetic transmission of its negative effects to offspring

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent condition characterized by persistent inattention, hyperactivity, and impulsivity, often leading to significant impairments in daily functioning. Numerous medications have been developed to manage ADHD, with methylphenidate (commonly known as Ritalin or Concerta) being the most widely used active compound. While methylphenidate (MPH) effectively improves attention, focus, and emotional regulation, its long-term use can lead to behavioral issues such as increased vigilance-stress response and anxiety, as well as physical side effects like sleep disturbances and decreased sensitivity to rewards. These side effects are more challenging to compensate for in adults compared to children, which may leave permanent effects. This study aims to investigate the long-term effects of MPH use in adult women, with a focus on its role in sleep disorders, circadian rhythm disruption, and the potential implications for pregnancy, specifically on the susceptibility of offspring to accelerated brain aging. Our hypothesis is that MPH use during pregnancy may contribute to changes in offspring telomere length and gene methylation patterns associated with brain aging, thereby increasing their vulnerability to neurodegeneration. To evaluate this, telomere length and methylation analyses were conducted on genes linked to brain aging in the second-generation offspring. Additionally, our hypothesis is that therapeutic interventions, such as melatonin for regulating sleep disturbances and oxytocin as an alternative to mitigate MPH’s side effects, may have protective effects. Zebrafish were used as the model organism in this study due to their high genetic similarity to humans and their ease of egg production, enabling multi-generational studies. As a result of this study, it was determined that neuroinflammation caused by circadian rhythm disruption and maternal stress due to MPH accumulation was reduced through melatonin & MPH and oxytocin & MPH combinational treatments. In the offspring of the next generation, it was observed that the telomere length inherited at birth was shorter when treated with MPH only. Also, methylation in the FOXM1 is observed in MPH-only treatment group, and compensated with combinational treatments for melatonin and oxytocin.