Cardiovascular afferents cause the release of 5‐HT in the nucleus tractus solitarii; this release is regulated by the low‐ (PMAT) not the high‐affinity transporter (SERT)

Key points The nucleus tractus solitarii (NTS) integrates visceral afferent information essential for cardiovascular haemostasis. Using fast‐cyclic voltammetry in anaesthetized rats, 5‐HT (serotonin) release was detected in NTS in response to activation of these afferents. Removal of 5‐HT from the extracellular space is usually regulated by the low‐capacity, high‐affinity 5‐HT transporter (5‐HTT/SERT). The present data demonstrate that 5‐HT removal in the NTS is regulated by the plasma membrane monoamine transporter (PMAT), a high‐capacity, low‐affinity transporter. The present data also demonstrate that the 5‐HT released by afferent activation comes from at least two different sources. It is suggested that one of these sources is the afferents themselves. These results demonstrate a physiological role for the low‐affinity uptake transporter in the regulation of 5‐HT concentration in NTS.Abstract The nucleus tractus solitarii (NTS) integrates inputs from cardiovascular afferents and thus is crucial for cardiovascular homeostasis. These afferents primarily release glutamate, although 5‐HT has also been shown to play a role in their actions. Using fast‐cyclic voltammetry, an increase in 5‐HT concentrations (range 12–50 n m ) could be detected in the NTS in anaesthetized rats in response to electrical stimulation of the vagus and activation of cardiopulmonary, chemo‐ and baroreceptor reflexes. This 5‐HT signal was not potentiated by the serotonin transporter (SERT) or the noradrenaline transporter (NET) inhibitors citalopram and desipramine (1 mg kg −1 ). However, decynium‐22 (600 μg kg −1 ), an organic cation 3 transporter (OCT3)/plasma membrane monoamine transporter (PMAT) inhibitor, increased the 5‐HT signal by 111 ± 21% from 29 ± 10 n m . The effectiveness of these inhibitors was tested against the removal time of 5‐HT and noradrenaline applied by microinjection to the NTS. Citalopram and decynium‐22 attenuated the removal of 5‐HT but not noradrenaline, whereas desipramine had the reverse action. The OCT3 inhibitor corticosterone (10 mg kg −1 ) had no effect. Blockade of glutamate receptors with topical kynurenate (10–50 n m ) reduced the vagally evoked 5‐HT signal by 50%, indicating that this release was from at least two sources. It is concluded that vagally evoked 5‐HT release is under the regulation of the high‐capacity, low‐affinity transporter PMAT, not the low‐capacity, high‐affinity transporter SERT. This is the first demonstration that PMAT may be playing a physiological role in the regulation of 5‐HT transmission and this could indicate that 5‐HT is acting, in part, as a volume transmitter within the NTS.