Involvement of serotonin 5-HT sub(3) receptors in the modulation of noradrenergic transmission by serotonin reuptake inhibitors: a microdialysis study in rat brain

• Published in: Psychopharmacology Vol. 229; no. 2; pp. 331 - 344
• Main Authors: Fernandez-Pastor, Begona, Ortega, Jorge E, Meana, JJavier
• Format: Journal Article
• Language: English
• Published: 01.09.2013
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-013-3112-y

Rationale: Selective serotonin reuptake inhibitors (SSRIs), in addition to being able to enhance serotonergic neurotransmission, are able to modulate other brain systems involved in depression. Objectives: 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 sub(max)=141 plus or minus 13 %) and simultaneously decreased NA in the PFC (E sub(max)=-46 plus or minus 7 %). In the local presence into the LC of the alpha sub(2)-adrenoceptor antagonist RS79948 (1 mu M), systemic citalopram increased NA in the LC (E sub(max)=157 plus or minus 25 %) and PFC (E sub(max)=175 plus or minus 24 %). Local citalopram (0.1-100 mu M) into the LC induced NA increase in the LC (E sub(max)=210 plus or minus 25 %) and decrease in the PFC (E sub(max)=-38 plus or minus 9 %). Local LC citalopram effect was abolished by LC presence of the 5-HT sub(3) receptor antagonist MDL72222 (1 mu M) but not the 5-HT sub(1/2) receptor antagonist methiothepin (1 mu M). Systemic citalopram in the LC presence of MDL72222 did not modify NA in the LC but increased NA in the PFC (E sub(max)=158 plus or minus 26 %). Local citalopram into the PFC enhanced NA (E sub(max)=376 plus or minus 18 %) in the area, which was prevented by MDL72222. Conclusions: The SSRI citalopram modulates central noradrenergic neurotransmission by activation, through endogenous serotonin, of 5-HT sub(3) receptors expressed in the somatodendritic (LC) and terminal (PFC) areas, which subsequently promote an enhancement of local NA. Therefore, 5-HT sub(3) receptors and somatodendritic alpha sub(2)-adrenoceptors in the LC play an important role in the global effect of SSRIs.