Fluoxetine potentiates methylphenidate-induced gene regulation in addiction-related brain regions: concerns for use of cognitive enhancers?
BACKGROUND
There is growing use of psychostimulant cognitive enhancers such as methylphenidate (Ritalin). Methylphenidate differs from the psychostimulant cocaine because it does not enhance synaptic levels of serotonin. We investigated whether exposure to methylphenidate combined with a serotonin-enhancing medication, the prototypical selective serotonin reuptake inhibitor (SSRI) fluoxetine (Prozac), would produce more "cocaine-like" molecular and behavioral changes.


METHODS
We measured the effects of fluoxetine on gene expression induced by the cognitive enhancer methylphenidate in the striatum and nucleus accumbens of rats, by in situ hybridization histochemistry. We also determined whether fluoxetine modified behavioral effects of methylphenidate.


RESULTS
Fluoxetine robustly potentiated methylphenidate-induced expression of the transcription factors c-fos and zif 268 throughout the striatum and to some degree in the nucleus accumbens. Fluoxetine also enhanced methylphenidate-induced stereotypical behavior.


CONCLUSIONS
Both potentiated gene regulation in the striatum and the behavioral effects indicate that combining the SSRI fluoxetine with the cognitive enhancer methylphenidate mimics cocaine effects, consistent with an increased risk for substance use disorder.
Steiner
Heinz
H
Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science, Chicago Medical School, North Chicago, Illinois, USA. Heinz.Steiner@rosalindfranklin.edu
Van Waes
Vincent
V
Marinelli
Michela
M
D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D001345:Autoradiography / Q000379:methods; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004357:Drug Synergism; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D018687:Antidepressive Agents, Second-Generation; D000697:Central Nervous System Stimulants; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D005473:Fluoxetine; D008774:Methylphenidate