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Chronic Combined Oral Methylphenidate and Fluoxetine Increases Inflammation in Somatosensory and Mesolimbic Brain Regions

Julianna Roeser,Huy Lu,Abigail M. Lantry,Caleigh Hoerner,George Lagamjis,Shannon Klein,Rania Ahmed,I. Elman,Albert Pinhasov,K. Blum,Michael Hadjiargyrou,David E. Komatsu,Panayotis K. Thanos

Published 2025 in Neurochemical Research

ABSTRACT

Methylphenidate (MP) is commonly prescribed to treat attention deficit hyperactivity disorder (ADHD). ADHD and depression are often comorbid, leading to simultaneous use of serotonin reuptake inhibitors (SSRIs), such as Fluoxetine (FLX). Previous studies have shown MP increases microglial activation, which has been linked to neuroinflammation, but little is known about these two medications in combination. To address this gap in our knowledge, 3-week-old male Sprague Dawley rats were randomly assigned into four groups receiving either water, MP, FLX, or MP + FLX orally using a previously established dosing regimen. After four weeks of treatment the animal’s brains were collected for in vitro [3H] PK11195 autoradiography. Chronic treatment with MP and MP + FLX resulted in significantly increased [3H] PK11195 binding in somatosensory regions including the cortex limbs somatosensory (S(Limbs)), facial somatosensory (S(Face)), dorsal caudate putamen (D CPU), and ventral caudate putamen (V CPU). Chronic treatment with MP increased microglial activation in specific brain regions; however, these effects were not amplified by co-administration with fluoxetine. These findings emphasize the importance of further investigating the interactions between SSRIs and MP, particularly as their combined use becomes more prevalent.

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