Chronic Co-administration of Methylphenidate and Fluoxetine Reduces Striatal NMDA Receptor Binding in Adolescent Rats

Methylphenidate (MP), a widely used medicine for attention deficit/hyperactivity disorder (ADHD), is commonly prescribed in combination with selective serotonin reuptake inhibitors (SSRI) e.g., fluoxetine (FLX). However, neurochemical effects of the MP + FLX combination have not been sufficiently elucidated. Given the pivotal role played by glutamatergic signaling in psychostimulant responses and corticostriatal plasticity, we employed a 2-level factorial design to assess how the individual treatments and their co-administration affect N-methyl-D-aspartate receptor (NMDAR) binding using [³H] MK-801 in vitro autoradiography. Three-week-old male rats were randomized into four groups: MP (30/60 mg/kg), FLX (20 mg/kg), MP + FLX (30/60 mg/kg and 20 mg/kg), and vehicle. Treatment was administered for four weeks using a dual bottle drinking paradigm that models human dosing and pharmacokinetics. Following the treatment, [³H] MK-801 in vitro autoradiography was performed on coronal brain sections. The MP + FLX group significantly decreased NMDA binding levels in the dorsal caudate-putamen (DCPU) (39%), ventral caudate-putamen (VCPU) (36%), and nucleus accumbens (Nac) (34%), compared to vehicle. Rats in the MP group demonstrated reduced NMDA binding in the DCPU only, and there were no significant differences in binding for the FLX group. These findings indicate that MP + FLX coadministration yields a reduction in NMDAR binding across the striatum, an effect not produced by either of the drugs. Thus, reduced NMDA binding following MP + FLX treatment may contribute to dysregulations in memory, motor, and reward systems. Further studies are warranted to evaluate the neurochemical, neurodevelopmental, and clinical correlates of MP + FLX glutamatergic effects in adolescent patients.