Long-term consequences of adolescent methylphenidate exposure on sustained attention and prelimbic PV+ interneuron...

Adolescence is a sensitive period for the maturation of prefrontal GABAergic circuitry, particularly involving parvalbumin-expressing (PV+) interneurons that regulate excitatory-inhibitory balance and support attentional control. Methylphenidate (MPH), widely prescribed for attention-deficit/hyperactivity disorder (ADHD, is commonly administered throughout adolescence, yet its long-term impact on PV+ interneuron development remains unclear. Here, we examined whether chronic MPH exposure during distinct adolescent windows (PD35-55, PD42-62, PD49-69) alters PV+ interneuron maturation in the prelimbic (PrL) cortex and produces enduring attentional impairments. Male and female Wistar rats received 5 mg/kg MPH for 20 consecutive days and, in adulthood (PD100), were tested in a sustained attention task (SAT) and its distractor variant (dSAT). MPH exposure produced a reduction in PV+ interneuron density in the PrL, but only treatment during late adolescence (PD49-69) disrupted the normal developmental increase in PV+ cells. This PV+ reduction interneurons was accompanied by persistent deficits in sustained attention, reflected by decreased hit rates and poor recovery under high attentional demand, while correct rejections remained intact. These findings identify late adolescence as a critical vulnerability window in which MPH disrupts prefrontal inhibitory maturation and is associated with altered adult attentional performance, highlighting the importance of developmental timing in psychostimulant exposure.