Extracellular Signal-Regulated Kinases Mediate an Autoregulation of GABAB-Receptor-Activated Whole-Cell Current in Locus Coeruleus Neurons

The norepinephrine-releasing neurons in the locus coeruleus (LC) are well known to regulate wakefulness/arousal. They display active firing during wakefulness and a decreased discharge rate during sleep. We have previously reported that LC neurons express large numbers of GABA B receptors (GABA B Rs) located at peri-/extrasynaptic sites and are subject to tonic inhibition due to the continuous activation of GABA B Rs by ambient GABA, which is significantly higher during sleep than during wakefulness. In this study, we further showed using western blot analysis that the activation of GABA B Rs with baclofen could increase the level of phosphorylated extracellular signal-regulated kinase 1 (ERK 1 ) in LC tissue. Recordings from LC neurons in brain slices showed that the inhibition of ERK 1/2 with U0126 and FR180204 accelerated the decay of whole-cell membrane current induced by prolonged baclofen application. In addition, the inhibition of ERK 1/2 also increased spontaneous firing and reduced tonic inhibition of LC neurons after prolonged exposure to baclofen. These results suggest a new role of GABA B Rs in mediating ERK 1 -dependent autoregulation of the stability of GABA B R-activated whole-cell current, in addition to its well-known effect on gated potassium channels, to cause a tonic current in LC neurons.