Figure 6.

The norepinephrine (NE) “hot spot” mechanism. (1A) Spillover glutamate (green dots) from highly active neurons interacts with nearby depolarized NE varicosities in a positive feedback loop involving NMDA and other glutamate receptors that leads to greater local NE release (maroon dots). The glutamatergic NMDA receptors require concomitant depolarization of noradrenergic axons (lightning symbol). Thus, hot spots amplify prioritized inputs most effectively under phasic arousal. (1B) Glutamate also recruits nearby astrocytes to release serine, glycine (orange dots), and additional glutamate. (2) Greater NE release creates concentration levels sufficient to activate low-affinity β-adrenoreceptors, which enhances neuron excitability. (3) Via activation of β and α2A auto-receptors, NE can stimulate or inhibit additional NE release, respectively. (4) Within hot spots, NE engages β-adrenoceptors on pre-synaptic glutamate terminals to increase glutamate release. (5) Finally, NE binding to post-synaptic β-adrenoceptors also inhibits the slow afterhypolarization, enabling the neuron to fire for even longer.