or β1 receptors. Interestingly, the effect of methylphenidate on firing rate was abolished when blockers of synaptic transmission were added to the bath suggesting that NE may suppress the activity of fast-spiking interneurons that normally regulate pyramidal neuron excitability. In addition to these findings, the effect of activating adrenergic receptors on NMDA EPSCs recorded from deep-layer pyramidal neurons in the rodent PFC has also been investigated. Norepinephrine itself reduced stimulus-evoked NMDA EPSCs and this effect was mimicked by both α1 and α2 receptors agonists (Liu et al., 2006). This study also demonstrated that adrenergic receptor suppression of NMDA responses involved different intracellular signaling pathways with α1 effects mediated via the PLC-IP3-Ca2+ pathway and α2 effects occurring through inhibition of the cAMP-PKA signal transduction process. The α1 calcium-mediated inhibition of PFC activity may also arise via activation of calcium-sensitive potassium channels (SK) that contribute to the regulation of the after-hyperpolarization. Hyperpolarization-activated cyclic-nucleotide gated channels (HCN) may reduce activity through shunting inhibition when levels of cAMP are high. Modulating these channels pharmacologically improves working memory performance in rodents consistent with the idea that optimal levels of NE signaling are required for proper PFC function (Arnsten, 2009).
