title: Involvement of serotonin 5-HT3 receptors in the modulation of noradrenergic transmission by serotonin reuptake inhibitors: a microdialysis study in rat brain.
abstract: BACKGROUND
  Selective serotonin reuptake inhibitors (SSRIs), in addition to being able to enhance serotonergic neurotransmission, are able to modulate other brain systems involved in depression.
  
  
  OBJECTIVE
  This study evaluates the neurochemical effect of the SSRI citalopram on brain noradrenergic activity and the serotonin receptor involved in this effect.
  
  
  METHODS
  Dual-probe microdialysis in the locus coeruleus (LC) and prefrontal cortex (PFC) was performed in freely awake rats.
  
  
  RESULTS
  Systemic citalopram (10 mg/kg, i.p.) increased noradrenaline (NA) in the LC (E max = 141 ± 13%) and simultaneously decreased NA in the PFC (Emax = -46 ± 7%). In the local presence into the LC of the α2-adrenoceptor antagonist RS79948 (1 μM), systemic citalopram increased NA in the LC (Emax = 157 ± 25%) and PFC (Emax = 175 ± 24%). Local citalopram (0.1-100 μM) into the LC induced NA increase in the LC (Emax = 210 ± 25%) and decrease in the PFC (Emax = -38 ± 9%). Local LC citalopram effect was abolished by LC presence of the 5-HT3 receptor antagonist MDL72222 (1 μM) but not the 5-HT1/2 receptor antagonist methiothepin (1 μM). Systemic citalopram in the LC presence of MDL72222 did not modify NA in the LC but increased NA in the PFC (Emax = 158 ± 26%). Local citalopram into the PFC enhanced NA (Emax = 376 ± 18%) in the area, which was prevented by MDL72222.
  
  
  CONCLUSIONS
  The SSRI citalopram modulates central noradrenergic neurotransmission by activation, through endogenous serotonin, of 5-HT3 receptors expressed in the somatodendritic (LC) and terminal (PFC) areas, which subsequently promote an enhancement of local NA. Therefore, 5-HT3 receptors and somatodendritic α2-adrenoceptors in the LC play an important role in the global effect of SSRIs.
authors: Department of Pharmacology, University of the Basque Country (UPV/EHU), Leioa, 48940, Bizkaia, Spain.
authors: Begoña
authors: B
authors: Fernández-Pastor
authors: Jorge E
authors: JE
authors: Ortega
authors: J Javier
authors: JJ
authors: Meana
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004563:Electrochemistry; D007546:Isoquinolines / Q000494:pharmacology; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009287:Naphthyridines / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology; D014851:Wakefulness
chemical_list: D007546:Isoquinolines; D009287:Naphthyridines; C104875:RS 79948-197; D044406:Receptors, Serotonin, 5-HT3; D018490:Serotonin Agents; D009638:Norepinephrine
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