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. Author manuscript; available in PMC: 2011 Jul 25.
Published in final edited form as: Expert Rev Neurother. 2010 Oct;10(10):1595–1605. doi: 10.1586/ern.10.133

Figure 2. A working model of norepinephrine actions at postsynaptic α-2A receptors in the prefrontal cortex.

Figure 2

(A) Prefrontal cortex (PFC) pyramidal cell networks interconnect on dendritic spines, exciting each other to maintain information, such as goals and rules, in working memory. Recent data have shown that cAMP signaling can weaken these connections by opening potassium channels on spines, which `shunt' network inputs by hyperpolarizing the spine. (B) An example of PFC neuronal firing in a monkey performing a working memory task. The top shows action potentials on seven different trials as the monkey fixates to do the trial, sees a visuospatial cue, remembers the spatial position over a short delay period and then responds to the location where the cue had been. The bottom raster shows the summed response to all seven trials. This neuron shows very little firing during the delay period due to the application of the α-2 receptor antagonist, yohimbine. A similar reduction in neuronal firing during the delay period is observed with the application of other drugs that increase or mimic cAMP signaling, for example, agents that mimic cAMP or reduce cAMP catabolism. The work of Bao-Ming Li has shown that infusion of yohimbine into the monkey PFC impairs working memory, induces locomotor hyperactivity, and weakens response inhibition on a Go/No-Go task (see text). It is possible that individuals with attention-deficit/hyperactivity disorder symptoms arising from reduced norepinephrine production also have weaker PFC regulation of behavior due to reduced PFC network firing. (C) By contrast, α-2A agonists, such as guanfacine, can enhance the physiological strength of PFC network connections by stimulating postsynaptic α-2A receptors. This reduces cAMP signaling by activating G proteins (Gi), which inhibit adenylyl cyclase, the enzyme that generates cAMP. The reduction in cAMP closes the potassium channels, and depolarizes the spine. This strengthens network connectivity. (D) Stimulation of α-2A receptors in the monkey PFC increases neuronal firing during the delay period when the animal is using working memory to remember a spatial location. Guanfacine has been shown to enhance a variety of PFC functions in rodents, monkeys and humans.

NE: Norepinephrine Adapted from [49].