Endogenous activation of serotonin-2A receptors is required for respiratory rhythm generation in vitro

Endogenous amines and peptides continuously modulate the activity of neuronal networks and are required even for their normal operation. The respiratory rhythm generator, localized in the pre-Bötzinger complex, is not an exception. This network is modulated by various neurotransmitters, including serotonin (5-HT). In this study, we isolated the respiratory network in brainstem slices and demonstrate that the endogenous activation of 5-HT(2A) is required for the generation of the respiratory rhythm in vitro. At the network level, activation of 5-HT(2A) receptors with 4-iodo-2,5-dimethoxyamphetamine or the 5-HT uptake blocker alaproclate increased the frequency of respiratory activity. Blockade of endogenously activated 5-HT(2A) receptors with three different antagonists decreased the frequency, amplitude, and regularity of respiratory population activity, an effect that was blocked by protein kinase C (PKC) activators. At the cellular level, blockade of 5-HT(2A) receptors reduced the action potential discharge in all examined respiratory neurons, which was associated with a reduction in the fast and the persistent sodium current. Continuous application of 5-HT(2A)-receptor antagonists differentially affected pacemaker neurons. Pacemaker activity was eliminated in cadmium-insensitive pacemaker neurons. In cadmium-sensitive pacemaker neurons, the frequency of pacemaker activity was unaffected and the amplitude of pacemaker bursts was enhanced. It is assumed that cadmium-insensitive pacemakers rely on the persistent sodium current, whereas cadmium-sensitive pacemakers depend on the activation of calcium currents. We conclude that endogenously activated 5-HT(2A) receptors are required for maintaining fictive respiratory activity in the brainstem slice by modulating sodium conductances via a PKC pathway.