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Fluoxetine Potentiates Oral Methylphenidate-Induced Gene Regulation in the Rat Striatum

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Abstract

Methylphenidate (MP) is combined with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (FLX) to treat various disorders. MP, a dopamine reuptake inhibitor, helps manage attention-deficit hyperactivity disorder (ADHD) and is abused as a cognitive enhancer; it has a reduced addiction liability. We showed that combining FLX (serotonin) with MP potentiates MP-induced gene regulation in the striatum. These studies used intraperitoneal drug administration, which is relevant for MP abuse. Clinically, MP and FLX are taken orally (slower bioavailability). Here, we investigated whether chronic oral administration of MP and FLX also altered striatal gene regulation. MP (30/60 mg/kg/day), FLX (20 mg/kg/day), and MP + FLX were administered in rats’ drinking water for 8 h/day over 4 weeks. We assessed the expression of dynorphin and substance P (both markers for striatal direct pathway neurons) and enkephalin (indirect pathway) by in situ hybridization histochemistry. Chronic oral MP alone produced a tendency for increased dynorphin and substance P expression and no changes in enkephalin expression. Oral FLX alone did not increase gene expression. In contrast, when given together, FLX greatly enhanced MP-induced expression of dynorphin and substance P and to a lesser degree enkephalin. Thus, FLX potentiated oral MP-induced gene regulation predominantly in direct pathway neurons, mimicking cocaine effects. The three functional domains of the striatum were differentially affected. MP + SSRI concomitant therapies are indicated in ADHD/depression comorbidity and co-exposure occurs with MP misuse as a cognitive enhancer by patients on SSRIs. Our findings indicate that MP + SSRI combinations, even given orally, may enhance addiction-related gene regulation.

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Data Availability

The data generated during the current study are available from the corresponding author on reasonable request.

Code Availability

Not applicable.

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Funding

This work was supported in part by the National Institutes of Health Grants DA046794 (H.S.) and HD070888 (P.K.T.) and the New York Research Foundation [Q0942016] (P.K.T.).

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Authors and Affiliations

  1. Stanson Toshok Center for Brain Function and Repair, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA

    Connor Moon & Heinz Steiner

  2. Behavioral Neuropharmacology and Neuroimaging Laboratory, Clinical Research Institute On Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University At Buffalo, Buffalo, NY, 14203, USA

    Matt Marion & Panayotis K. Thanos

  3. Discipline of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL, 60064, USA

    Heinz Steiner

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Heinz Steiner and Panayotis K. Thanos were responsible for study design; Matt Marion and Connor Moon performed the experimental studies and data collection; Connor Moon, Matt Marion, Panayotis K. Thanos, and Heinz Steiner contributed to data analysis; Heinz Steiner wrote the first draft of the manuscript, and all authors commented on and approved the manuscript.

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Correspondence to Heinz Steiner.

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All experimental procedures followed the guidelines as described in the “Guide for the Care and Use of Laboratory Rats” (National Academy of Science and NRC, 1996) and were approved by the State University at Buffalo Institutional Animal Care and Use Committee.

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Moon, C., Marion, M., Thanos, P.K. et al. Fluoxetine Potentiates Oral Methylphenidate-Induced Gene Regulation in the Rat Striatum. Mol Neurobiol 58, 4856–4870 (2021). https://doi.org/10.1007/s12035-021-02466-y

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  • DOI: https://doi.org/10.1007/s12035-021-02466-y

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