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

This is the authors' abstract. We don't add key points for this paper.

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.