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

Selective serotonin reuptake inhibitors (SSRIs), in addition to being able to enhance serotonergic neurotransmission, are able to modulate other brain systems involved in depression. This study evaluates the neurochemical effect of the SSRI citalopram on brain noradrenergic activity and the serotonin receptor involved in this effect. Dual-probe microdialysis in the locus coeruleus (LC) and prefrontal cortex (PFC) was performed in freely awake rats. Systemic citalopram (10 mg/kg, i.p.) increased noradrenaline (NA) in the LC (E ^sub max^=141±13 %) and simultaneously decreased NA in the PFC (E^sub max^=-46±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±25 %) and PFC (E^sub max^=175±24 %). Local citalopram (0.1-100 [mu]M) into the LC induced NA increase in the LC (E^sub max^=210±25 %) and decrease in the PFC (E^sub max^=-38±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±26 %). Local citalopram into the PFC enhanced NA (E^sub max^=376±18 %) in the area, which was prevented by MDL72222. 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.[PUBLICATION ABSTRACT]