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Methylphenidate with or without fluoxetine triggers reinstatement of cocaine seeking behavior in rats

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Abstract

Methylphenidate (MP) is commonly prescribed to treat attention-deficit hyperactivity disorder (ADHD). MP is also taken for non-medical purposes as a recreational drug or “cognitive enhancer”. Combined exposure to MP and selective serotonin reuptake inhibitors such as fluoxetine (FLX) can also occur, such as in the treatment of ADHD with depression comorbidity or when patients taking FLX use MP for non-medical purposes. It is unclear if such exposure could subsequently increase the risk for relapse in former cocaine users. We investigated if an acute challenge with MP, FLX, or the combination of MP + FLX could trigger reinstatement of cocaine seeking behavior in a model for relapse in rats. Juvenile rats self-administered cocaine (600 µg/kg/infusion, 1–2 h/day, 7–8 days) and then underwent extinction and withdrawal during late adolescence-early adulthood. Reinstatement was tested at a low dose of MP (2 mg/kg, I.P., comparable to doses used therapeutically) or a high dose of MP (5 mg/kg, comparable to doses used recreationally or as a cognitive enhancer), with or without FLX (2.5–5 mg/kg, I.P.). An acute challenge with the high dose of MP (5 mg/kg), with or without FLX, reinstated cocaine seeking behavior to levels comparable to those seen after an acute challenge with cocaine (15 mg/kg, I.P.). The low dose of MP (2 mg/kg) with or without FLX did not reinstate cocaine seeking behavior. Our results suggest that acute exposure to a high dose of MP, with or without FLX, may increase the risk for relapse in individuals who used cocaine during the juvenile period.

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Fig. 1: Effects of Vehicle (n = 9), MP2 (n = 6), or MP5 (n = 8) on seeking behavior during a within-session extinction/reinstatement test.
Fig. 2: Effects of Vehicle, FLX5, MP5, FLX5 + MP5, or COC15 administered sequentially in the same rats on seeking behavior during a between-session extinction/reinstatement test (n = 6).
Fig. 3: Effects of Vehicle, FLX2.5 (n = 6), FLX5 (n = 7), MP2 (n = 13), MP2 + FLX2.5 (n = 9), MP2 + FLX5 (n = 11), MP5 (n = 11), MP5 + FLX.2.5 (n = 9), MP5 + FLX5 (n = 6), or COC15 (n = 10) on seeking behavior during a between-sessions extinction/reinstatement test.

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Funding

Funding

This work was supported by National Institute on Drug Abuse Grants R21 DA031916 to MM and R01 DA046794 to HS.

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Authors and Affiliations

  1. Discipline of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA

    Lorissa Lamoureux, Joel Beverley, Heinz Steiner & Michela Marinelli

  2. Biologic Resources Laboratory, University of Illinois at Chicago, Chicago, IL, USA

    Lorissa Lamoureux

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

    Heinz Steiner

  4. Department of Neuroscience and the Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA

    Michela Marinelli

  5. Department of Neurology, Department of Psychiatry and Behavioral Science, and the Mulva Clinic for the Neurosciences, Dell Medical School, University of Texas at Austin, Austin, TX, USA

    Michela Marinelli

  6. Division of Pharmacology and Toxicology, College of Pharmacy, the University of Texas at Austin, Austin, TX, USA

    Michela Marinelli

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  1. Lorissa Lamoureux
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  2. Joel Beverley
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  4. Michela Marinelli
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Contributions

Conception and design of the study: MM and HS. Acquisition of the work: LL, JB and MM. Analysis of the data: MM and HS. Drafting and revising of the manuscript: MM and HS.

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Correspondence to Michela Marinelli.

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Lamoureux, L., Beverley, J., Steiner, H. et al. Methylphenidate with or without fluoxetine triggers reinstatement of cocaine seeking behavior in rats. Neuropsychopharmacol. 49, 953–960 (2024). https://doi.org/10.1038/s41386-023-01777-z

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