title: Chronic 5-HT transporter blockade reduces DA signaling to elicit basal ganglia dysfunction.
abstract: Serotonin (5-HT)-selective reuptake inhibitors (SSRIs) are widely administered for the treatment of depression, anxiety, and other neuropsychiatric disorders, but response rates are low, and side effects often lead to discontinuation. Side effect profiles suggest that SSRIs inhibit dopaminergic activity, but mechanistic insight remains scarce. Here we show that in mice, chronic 5-HT transporter (5-HTT) blockade during adulthood but not during development impairs basal ganglia-dependent behaviors in a dose-dependent and reversible fashion. Furthermore, chronic 5-HTT blockade reduces striatal dopamine (DA) content and metabolism. A causal relationship between reduced DA signaling and impaired basal ganglia-dependent behavior is indicated by the reversal of behavioral deficits through L-DOPA administration. Our data suggest that augmentation of DA signaling would reduce side effects and increase efficacies of SSRI-based therapy.
authors: Division of Developmental Neuroscience, Department of Psychiatry, Columbia University, New York, New York 10032, USA.
authors: Emanuela
authors: E
authors: Morelli
authors: Holly
authors: H
authors: Moore
authors: Tahilia J
authors: TJ
authors: Rebello
authors: Neil
authors: N
authors: Gray
authors: Kelly
authors: K
authors: Steele
authors: Ennio
authors: E
authors: Esposito
authors: Jay A
authors: JA
authors: Gingrich
authors: Mark S
authors: MS
authors: Ansorge
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001479:Basal Ganglia / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D002452:Cell Count; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005106:Exploratory Behavior / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology* / Q000627:therapeutic use; D006719:Homovanillic Acid / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009069:Movement Disorders / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D011597:Psychomotor Performance / Q000187:drug effects; D011897:Random Allocation; D045442:Rotarod Performance Test; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects
chemical_list: D015102:3,4-Dihydroxyphenylacetic Acid; D004298:Dopamine; D015259:Dopamine Agents; D005473:Fluoxetine; D006719:Homovanillic Acid; D007980:Levodopa; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors