Respiratory motor output adapts to regulate blood gases. One form of adaptive plasticity is long-term facilitation of respiratory motor output induced in vivo in adult and neonatal rats by episodic hypoxia. We have identified an in vitro form of long-term facilitation (ivLTF) in hypoglossal (XII) motoneurones, a 50-70% increase in XII nerve output and 30-55% increase in inspiratory drive currents in XII motoneurones persisting for >1 hr. ivLTF is induced preferentially by episodic, rather than continuous, application of 5 HT₂ & α₁-adrenergic agonists and requires coincident activation of Group 1 metabotropic glutamate receptors. Experiments were performed on medullary slice preparations from neonatal Sprague-Dawley rats (P0-P3) that generate a respiratory-related rhythm. Rats were anaesthetised with isoflurane, rapidly decerebrated and the brainstem-spinal cord removed. A medullary slice containing the preBötzinger Complex was cut and superfused with ACSF (28°C, [K⁺] 9 mM). XII motor output was recorded from the cut ends of XII nerve rootlets with a suction electrode. Whole-cell voltage clamp recordings (V_h=-70 mV) were made from XII motoneurones identified by location and presence of endogenous inspiratory currents. For synaptic isolation, TTX (1 μM) was added to the bath and AMPA (10 μM), in an ejection pipette positioned over the motoneuronal soma, was pressure ejected and exogenous currents recorded. To induce ivLTF we bath applied, in 3×3 min episodes spaced 5 min apart either 1 μM α-Me-5-HT or 10 μM phenylephrine. A major component of ivLTF is postsynaptic potentiation of motoneuronal AMPA receptors, as exogenous AMPA currents are potentiated in synaptically isolated motoneurones. Protein kinase C and MAPK activity but not PKA activity is required for ivLTF, with PKG having a modulatory role. An additional requirement for ivLTF is the activation of TrkB receptors by BDNF, possibly involving rapid protein synthesis. We propose that this type of plasticity underlies important forms of motoneuronal adaptive learning and may increase upper airway muscle tone contributing to the maintenance of upper airway patency. The fact that these changes occur in motoneurones clearly indicates that plasticity critical for behaviour is a general property of mammalian neurones.