Regulation of central noradrenergic activity by 5-HT3 receptors located in the locus coeruleus of the rat

A functional interaction between serotonergic and noradrenergic systems has been shown in the locus coeruleus (LC). Noradrenaline (NA) levels in the prefrontal cortex (PFC) are dependent on the firing rate of LC neurons, which is controlled by α2 adrenoceptors (α2ADR). The aim of the present study was to investigate the role of 5-HT3 receptors (5HT3R) in the modulation of central noradrenergic activity. We measured extracellular NA concentrations in the LC and PFC by dual-probe microdialysis in awake rats and the firing rate of LC neurons by electrophysiological techniques in vitro. Administration of the 5HT3R agonists SR57227 (1–100 μM) and m-chlorophenylbiguanide (mCPBG, 1–100 μM) into the LC increased NA in this nucleus (Emax = 675 ± 121% and Emax = 5575 ± 1371%, respectively) and decreased NA in the PFC (Emax = −49 ± 6% and Emax = −25 ± 11%, respectively). Administration of the 5HT3R antagonist Y25130 (50 μM) into LC attenuated SR57227 effect in the LC (Emax = 323 ± 28%) and PFC (Emax = −37 ± 7%). The α2ADR antagonist RS79948 (1 μM) blocked the SR57227 effect in the PFC but it did not change the effect in the LC (Emax = 677 ± 202%). In electrophysiological assays, both mCPBG (1–10 μM) and SR57227 (1–10 μM) reduced the firing rate of about 50% of tested LC neurons (maximal effect = −37 ± 2% and −31 ± 4%, respectively); this effect was partially blocked by Y25130 (50 μM). Administration of RS79948 (1 μM) reversed the inhibition induced by mCPBG. Competition radioligand assays against [3H]UK14304 and [3H]RX821002 (α2ADR selective drugs) in the rat brain cortex showed a very weak affinity of SR57227 for α2ADR, whereas the affinity of mCPBG for α2ADR was 17-fold higher than that of SR57227 for α2ADR. The present results suggest that 5HT3R stimulate NA release in the LC, which promotes simultaneously a decrease in the firing rate of LC neurons through α2ADR and then a decrease of NA release in terminal areas such as the PFC.

► We investigated the role of 5-HT3 receptors in the modulation of LC noradrenergic system.
► NA levels were measured by microdialysis and neuron firing rate was recorded by electrophysiology.
► Activation of 5HT3R increased NA in the LC, but reduced LC cell firing activity and NA in the PFC.
► An α2ADR antagonist blocked 5HT3R-mediated reduction in the LC cell firing and NA in the PFC.
► Thus, 5HT3R may reduce NA in the PFC by increasing NA in the LC and reducing cell activity through α2ADR.