Postsynaptic Effect of NE and LC Stimulation

1. Effect on Neuronal Discharge

The postsynaptic effects of NE have been studied in several target structures of the LC, such as the neocortex, hippocampus, and thalamus. The impact of LC on the electrophysiological activity of its target neurons was assessed by in vivo or in vitro application of noradrenergic agonists or antagonists and by in vivo LC activation.

Numerous studies have been conducted on the spontaneous and sensory-evoked responses of the neocortical neurons, indicating that NE application or LC stimulation is particularly efficient to enhance the responsiveness of these neurons to sensory stimulation. Indeed, NE does not change the amplitude of evoked potentials but reduces the spontaneous activity of neocortical target cells via both excitatory and inhibitory inputs. Altogether, NE seems to enhance the signal-to-noise ratio of sensory-evoked responses, thus making salient new features of the environment. More recently, noradrenergic activation was found to "gate" inputs to target neurons, which means that subthres-hold synaptic inputs become suprathreshold in the presence of NE.

Similarly, facilitory NE effects were demonstrated on various types of synaptically elicited activity in the hippocampus. In addition to these effects, there have been numerous demonstrations of NE enhancement of long-term potentiation in CA3 and the dentate gyrus.

2. Effects on Electroencephalograms (EEG)

Activation of LC neurons by local application of cholinergic agonists induces a desynchronization of cortical EEG, characterized by a shift to high-frequency, low-amplitude activity. This desynchroni-zation is generally considered as an index of sensory a a

dephosphory lation sequestration

Figure 7 b-Adrenergic receptor desensitization. (A) b-Adrenergic stimulation by NE results in the activation of adenylyl cyclase and the transformation of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). cAMP stimulates protein kinase A (PKA). Activated PKA phosphorylates the b-adrenergic receptor, which results in the uncoupling of the receptor from the G-protein. PKA also destabilizes the receptor mRNA and activates the transcription of its gene via the promoter cAMP-responsive element (CRE). Abbreviations: GTP, guanosine triphosphate; GDP, guanosine diphosphate. (B) Stimulated b-adrenergic receptor can also be phosphorylated by the b-adrenergic receptor kinase (b-ARK). A cytosolic protein, arrestin, binds to the phosphorylated receptor, provoking the uncoupling of the receptor from the G-protein and its sequestration in a clathrin-coated vesicle. Following its internalization, the receptor conformation adapts to the low pH maintained in the vesicle. Arrestin separates from the receptor, allowing its dephosphorylation by the G-protein-coupled receptor phosphatase (GRP) present in the membrane and its reexpression to the cell surface.

dephosphory lation sequestration

Figure 7 b-Adrenergic receptor desensitization. (A) b-Adrenergic stimulation by NE results in the activation of adenylyl cyclase and the transformation of adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). cAMP stimulates protein kinase A (PKA). Activated PKA phosphorylates the b-adrenergic receptor, which results in the uncoupling of the receptor from the G-protein. PKA also destabilizes the receptor mRNA and activates the transcription of its gene via the promoter cAMP-responsive element (CRE). Abbreviations: GTP, guanosine triphosphate; GDP, guanosine diphosphate. (B) Stimulated b-adrenergic receptor can also be phosphorylated by the b-adrenergic receptor kinase (b-ARK). A cytosolic protein, arrestin, binds to the phosphorylated receptor, provoking the uncoupling of the receptor from the G-protein and its sequestration in a clathrin-coated vesicle. Following its internalization, the receptor conformation adapts to the low pH maintained in the vesicle. Arrestin separates from the receptor, allowing its dephosphorylation by the G-protein-coupled receptor phosphatase (GRP) present in the membrane and its reexpression to the cell surface.

Figure 8 NE pharmacology. Several pharmacological agents are able to modify the noradrenergic transmission. a-Methyltyrosine inhibits tyrosine hydroxylase (TH). Reserpine provokes the release of NE from the synaptic vesicles. Desipramine and cocaine inhibit NE re-uptake by the NE transporter (NET). Amphetamine promotes reverse transport through the NET. Pargyline and many antidepressants (called MAOI for monoamine oxidase inhibitors) block the degradation of NE by monoamine oxidase (MAO). Prazosin, yohimbine, and propranolol (among others) inhibit the action of NE on al-, a2-, and b-adrenergic receptors, respectively. Phenylephrine, clonidine, and isoproterenol stimulate al-, a2-, and b-adrenergic receptors, respectively. The action of clonidine or yohimbine on a2-adrenergic autoreceptors also results in the inhibition or activation, respectively, of noradrenergic neuron firing and NE release. Finally, morphine inhibits noradrenergic neuron firing via somatodendritic m-opiate receptors.

perception. Conversely, LC inactivation by local or peripheral clonidine administration induces a shift in neocortical EEG to low-frequency, large-amplitude activity. Whereas LC innervates the cerebral cortex, the influence of LC on cortical EEG at least partly results from the stimulation of b-adrenergic receptors in the medial septum-diagonal band of Broca, a region that receives dense noradrenergic innervation from the LC.

Long-latency components of event-related potentials include the positive potentials recorded approximately 300 msec (P300) after the occurrence of novel or attention-eliciting events. These P300-like potentials are often considered as electrophysiological correlates ofhuman cognition. Although the electrolytic destruction of LC cells disrupts P300 potentials, this effect is not observed following specific 6-hydroxydopamine chemical destruction of noradrenergic ascending fibers. It is, therefore, possible that non-noradrenergic cells located in or passing through the LC may act in synergy with noradrenergic neurons.

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