Fluoxetine potentiation of methylphenidate-induced neuropeptide expression in the striatum occurs selectively in direct pathway (striatonigral) neurons.
Concomitant therapies combining psychostimulants such as methylphenidate and selective serotonin reuptake inhibitors (SSRIs) are used to treat several mental disorders, including attention-deficit hyperactivity disorder/depression comorbidity. The neurobiological consequences of these drug combinations are poorly understood. Methylphenidate alone induces gene regulation that mimics partly effects of cocaine, consistent with some addiction liability. We previously showed that the SSRI fluoxetine potentiates methylphenidate-induced gene regulation in the striatum. The present study investigated which striatal output pathways are affected by the methylphenidate + fluoxetine combination, by assessing effects on pathway-specific neuropeptide markers. Results demonstrate that fluoxetine (5 mg/kg) potentiates methylphenidate (5 mg/kg)-induced expression of substance P and dynorphin, markers for direct pathway neurons. In contrast, no drug effects on the indirect pathway marker enkephalin were found. Because methylphenidate alone has minimal effects on dynorphin, the potentiation of dynorphin induction represents a more cocaine-like effect for the drug combination. On the other hand, the lack of an effect on enkephalin suggests a greater selectivity for the direct pathway compared with psychostimulants such as cocaine. Overall, the fluoxetine potentiation of gene regulation by methylphenidate occurs preferentially in sensorimotor striatal circuits, similar to other addictive psychostimulants. These results suggest that SSRIs may enhance the addiction liability of methylphenidate.
Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science/The Chicago Medical School, North Chicago, IL 60064, USA.
Vincent
V
Van Waes
Betsy
B
Carr
Joel A
JA
Beverley
Heinz
H
Steiner
D000818:Animals; D001345:Autoradiography; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology* / Q000187:drug effects; D004357:Drug Synergism; D004399:Dynorphins / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology; D009434:Neural Pathways / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013373:Substance P; D013378:Substantia Nigra / Q000166:cytology / Q000502:physiology
D000697:Central Nervous System Stimulants; D004399:Dynorphins; D051766:Early Growth Response Protein 1; D004745:Enkephalins; D005473:Fluoxetine; D008774:Methylphenidate; D009479:Neuropeptides; D016760:Proto-Oncogene Proteins c-fos; D017367:Selective Serotonin Reuptake Inhibitors; D013373:Substance P