PT  - JOURNAL ARTICLE
AU  - Diana Lupu
AU  - Mukesh K Varshney
AU  - Daniel Mucs
AU  - Jose Inzunza
AU  - Ulf Norinder
AU  - Felicia Loghin
AU  - Ivan Nalvarte
AU  - Joelle Ruegg
TI  - Fluoxetine affects differentiation of midbrain dopaminergic neurons in vitro
AID  - 10.1124/mol.118.112342
DP  - 2018 Jan 01
TA  - Molecular Pharmacology
PG  - mol.118.112342
4099  - http://molpharm.aspetjournals.org/content/early/2018/08/16/mol.118.112342.short
4100  - http://molpharm.aspetjournals.org/content/early/2018/08/16/mol.118.112342.full
AB  - Recent meta-analyses found an association between prenatal exposure to the antidepressant fluoxetine (FLX) and an increased risk of autism in children. This developmental disorder has been related to dysfunctions in the brains' rewards circuitry, which, in turn, has been linked to dysfunctions in dopaminergic (DA) signalling. The present study investigated if FLX affects processes involved in dopaminergic neuronal differentiation. Mouse neuronal precursors were differentiated into midbrain dopaminergic precursor cells (mDPCs) and concomitantly exposed to clinically relevant doses of FLX. Subsequently, dopaminergic precursors were evaluated for expression of differentiation and stemness markers using qPCR. FLX treatment led to increases in early regional specification markers Orthodenticle homeobox 2 (Otx2) and Homeobox engrailed-1 and 2 (En1 and En2). On the other hand, two transcription factors essential for midbrain dopaminergic (mDA) neurogenesis, LIM Homeobox transcription factor 1 alpha (Lmx1a) and Paired-like homeodomain transcription factor 3 (Pitx3) were down-regulated by FLX treatment. The stemness marker Nestin (Nes) was increased, whereas the neuronal differentiation marker β3-tubulin (Tubb3) decreased. Additionally, we observed that FLX modulates the expression of several genes associated with ASD and down-regulates the estrogen receptors (ERs) α and β. Further investigations using ERβ knock-out (BERKO) mDPCs showed that FLX had no or even opposite effects on several of the genes analyzed, and that FLX may putatively bind directly to the ERs. These findings suggest that FLX affects differentiation of the dopaminergic system by increasing production of dopaminergic precursors, yet decreasing their maturation, partly via interference with the estrogen system.