Agonist of 5-HT1A/7 receptors but not that of 5-HT2 receptors disinhibits tracheobronchial-projecting airway vagal preganglionic neurons of rats

The vagus nerves supply the major cholinergic tone to airway smooth muscles physiologically and play critical roles in the genesis of airway hyperreactivity under some pathological conditions. Postganglionic airway cholinergic tone relies largely on the ongoing activity of medullary airway vagal preganglionic neurons (AVPNs), of which the tracheobronchial-projecting ones are primarily located in the external formation of the nucleus ambiguus (eNA). AVPNs are regulated by 5-HT, and 5-HT1A/7 and 5-HT2 receptors have been indicated to be involved. But the mechanisms at synaptic level are unknown. In the present study, tracheobronchial-projecting AVPNs (T-AVPNs) were retrogradely labeled from the trachea wall; fluorescently labeled T-AVPNs in the eNA were recorded with whole-cell voltage patch clamp; and the effects of 5-HT1A/7 receptor agonist (±)-8-Hydroxy-2-(dipropylamino) tetralin hydrobromide (8-OH-DPAT) (1 μmol L−1) and 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (10 μmol L−1) on the synaptic inputs were examined. 8-OH-DPAT significantly inhibited the GABAergic and glycinergic spontaneous inhibitory postsynaptic currents (sIPSCs) of T-AVPNs in both the frequency and amplitude but had no effect on the GABAergic and glycinergic miniature inhibitory postsynaptic currents (mIPSCs). The 8-OH-DPAT inhibition of the GABAergic and glycinergic sIPSCs was prevented by 5-HT1A/7 receptor antagonist N-[2-[4-(2-Methoxyphenyl)-1-piperazinyl] ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY-100635) (1 μmol L−1). 8-OH-DPAT had no effect on the glutamatergic spontaneous excitatory postsynaptic currents (sEPSCs) and caused no alterations in the baseline current and input resistance of T-AVPNs. DOI had no effect on any types of the synaptic inputs of T-AVPNs. These results suggest that 5-HT1A/7 receptor agonist causes “disinhibition” of T-AVPNs, which might, in part, account for the reflex increase of airway resistance.

▶8-OH-DPAT inhibits the frequency and amplitude of GABAergic sIPSCs of T-AVPNs. ▶8-OH-DPAT inhibits the frequency and amplitude of glycinergic sIPSCs of T-AVPNs. ▶8-OH-DPAT has no effect on the glutamatergic sEPSCs of T-AVPNs. ▶8-OH-DPAT has no effect on the GABAergic and glycinergic mIPSCs of T-AVPNs. ▶WAY-100635 blocks 8-OH-DPAT inhibition of GABAergic and glycinergic sIPSCs.