Involvement of serotonin 5-HT3 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: Fernández-Pastor, Begoña, Ortega, Jorge E., Meana, J. Javier
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2013
• Subjects: Analysis of Variance; Animals; Area Under Curve; Biomedical and Life Sciences; Biomedicine; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drug Interactions; Electrochemistry; Isoquinolines - pharmacology; Locus Coeruleus - drug effects; Locus Coeruleus - metabolism; Male; Microdialysis; Naphthyridines - pharmacology; Neurosciences; Norepinephrine - metabolism; Original Investigation; Pharmacology/Toxicology; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Psychiatry; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT3 - metabolism; Serotonin Agents - pharmacology; Wakefulness; Microdialysis; SSRIs; receptors; Antidepressants; Prefrontal cortex; 5-HT; Noradrenaline; Locus coeruleus; Citalopram
• 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 max  = 141 ± 13 %) and simultaneously decreased NA in the PFC (E max  = −46 ± 7 %). In the local presence into the LC of the α 2 -adrenoceptor antagonist RS79948 (1 μM), systemic citalopram increased NA in the LC (E max  = 157 ± 25 %) and PFC (E max  = 175 ± 24 %). Local citalopram (0.1–100 μM) into the LC induced NA increase in the LC (E max  = 210 ± 25 %) and decrease in the PFC (E max  = −38 ± 9 %). Local LC citalopram effect was abolished by LC presence of the 5-HT 3 receptor antagonist MDL72222 (1 μM) but not the 5-HT 1/2 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 (E max  = 158 ± 26 %). Local citalopram into the PFC enhanced NA (E max  = 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-HT 3 receptors expressed in the somatodendritic (LC) and terminal (PFC) areas, which subsequently promote an enhancement of local NA. Therefore, 5-HT 3 receptors and somatodendritic α 2 -adrenoceptors in the LC play an important role in the global effect of SSRIs.