Combined Chronic Oral Methylphenidate and Fluoxetine Decreases D2R Levels in the Caudate Putamen and Nucleus Accumbens

Abstract

Methylphenidate (MP) is a commonly prescribed psychostimulant for treating Attention-Deficit/Hyperactive Disorder (ADHD). Many patients with ADHD also experience anxiety and depression, often leading to co-dosing with selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (FLX), commonly used for ADHD-related and adolescent depression. Our laboratory and others have shown that MP increases striatal dopamine (DA) transporters and DA type 1 receptor binding (D1R) in rats, and FLX has been shown to affect the DA reward pathway through the effect DA receptors play on increased cellular serotonin (5-HT). However, the effects of combined MP and FLX on DA receptor binding remain unclear. This study investigated how MP, FLX, and their combination affect D1R and DA type 2 (D2R) binding. At three weeks of age, adolescent rats received four weeks of oral drug treatments via a previously established dosing paradigm that replicates human pharmacokinetics. Rats were separated into four groups, receiving water, MP, FLX, or MP + FLX. Following treatment, autoradiography binding was conducted on coronal brain sections and showed chronic combined treatment with MP + FLX resulted in significant decreases in D2R levels relative to controls in the: Dorsal Caudate Putamen (DCPU) (51.5%), Dorsolateral Caudate Putamen (DLCPU) (50.4%), Nucleus Accumbens Core (Nac Core) (44.8%), Ventral Caudate Putamen (VCPU) (47.7%), and Ventromedial Caudate Putamen (VMCPU) (49.1%). No significant effects were reported for D1R binding. Thus, the combined treatment of MP + FLX in attenuating D2R levels may be involved in the mechanism that prior literature has described an increased risk for substance use disorder, cognitive deficits and motor dysregulation.