Norepinephrine synaptic transmission

An overview of some of the processes involved in synaptic transmission is shown in Figure 10-1. Many of the processes are discussed below or in other chapters of this book. Many different types of substance are neurotransmitters. Classical neurotransmitters, such as ACh (see Ch. 11) and norepinephrine (NE see Ch. 12), are low-molecular-weight substances that have no other function but to serve as neurotransmitters. The predominant excitatory neurotransmitter in the brain, glutamate, and the inhibitory neurotransmitter in the spinal cord, glycine, are common and essential amino acids (see Chs 15 and 16). 

Reserpine and iproniazid research led to the monoamine hypothesis of depression. This hypothesis proposed that a reduction in the monoamine neurotransmitters caused depression. As described in the sidebar on pages 82-83, only a small number of neurons use serotonin as a neurotransmitter, but these cells project to widespread regions of the brain. The same holds true for norepinephrine and dopamine. Although not widely used in the nervous system, these neurotransmitters are apparently involved in networks of neurons that greatly influence a person s mood. Synaptic transmission between neurons in other areas of the brain—such as neurons that process visual information, for instance—often carry specific messages, such as the presence of an object at a certain point in the person s visual field. In contrast, the monoamine neurotransmitters underlie information processing of a more general nature, some of which correlates with mood. 

Synaptic transmission requires the release of neurotransmitters into the extracellular space to bind pre-or postsynaptic receptors, conveying a chemical message to nerve cells (Torres et al 2003a). Termination of this signaling occurs rapidly by uptake of the released neurotransmitter into the presynaptic cell by high-affinity neurotrans-mitter transporters. The clearance of the monoamines dopamine, norepinephrine, and serotonin occurs via the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT), respectively (Torres et al., 2003a)... 

Norepinephrine modulates many behavioral, cognitive, and physiological functions [72, 73], The catecholamine neurotransmitters dopamine and norepinephrine are stored in synaptic vesicles prior to release from the cell. It is within these vesicles that DpH is localized. Although most of the DpH is bound to the membrane of the vesicles, some DpH is free and is co-released with the catecholamines during synaptic transmission from neurons and into the blood from neurosecretory cells of the adrenal medulla [74], The levels found in serum are highly correlated between sibs, but varies between unrelated subjects [75], This variation has been found to be heritable in family and twin studies in both serum and CSF [76]. 

The subcellular localization of the enzyme is interesting. In contrast to tyrosine hydroxylase, which is localized to the cytoplasmic compartment, dopamine hydroxylase is largely contained within the aminergic storage vesicles. Thus, it appears that dopamine, which is synthesized in the cytosol, must be taken up into these vesicles in order to be converted to norepinephrine. Approximately 50% of the enzyme is associated with the membranous portion of the vesicles, whereas the other 50% is in a soluble form within the vesicle. During synaptic transmission noradrenergic neurons release both norepinephrine and its biosynthetic enzyme by an exocytotic mechanism. While most of the released norepinephrine is taken back up by the terminal, the enzyme is believed to diffuse of the synaptic cleft into the extracellular fluid and eventually into the serum. There are relatively large amounts of dopamine p-hydroxylase in human serum that are believed to arise from release from sympathetic neurons. 

Norepinephrine (7.5) is the transmitter at sympathetically innervated end-organs (see Table 7.1). After initiating synaptic transmission, it is inactivated mainly by reabsorption into the synaptosomes of the presynaptic terminal which secreted it (Iversen, 1967). A little of the norepinephrine is metabolized, in the neurons by monoamine oxidase, and extraneuronally by catechol-0-methyltransferase which effects 3-0 methylation. Norepinephrine can be saved from the destructive action of these two enzymes by, respectively, phenelzine (9.46) and pyrogallol. The four kinds of receptors for norepinephrine are described in Section 12.4. 

BZ is usually disseminated as an aerosol with the primary route of entry into the body through the respiratory system the secondary route is through the digestive tract. BZ blocks the action of acetylcholine in both the peripheral and central nervous systems. As such, it lessens the degree and extent of the transmission of impulses from one nerve fiber to another through their connecting synaptic junctions. It stimulates the action of noradrenaline (norepinephrine) in the brain, much as do amphetamines and cocaine. Thus, it may induce vivid hallucinations as it sedates the victim. Toxic delirium is very common. 

The CNS also contains a descending system for control of pain transmission. This system originates in the brain and can inhibit synaptic pain transmission at the dorsal horn. Important neurotransmitters here include endogenous opioids, serotonin, norepinephrine, y-aminobutyric acid, and neurotensin. 

A fourth modification of the classical model involves nitric oxide (NO), a new form of nonsynaptic interneuronal communication, or volume transmission. Nitric Oxide inhibits the uptake of dopamine, norepinephrine (Lonart and Johnson, 1994), and serotonin (Asano et ah, 1997) into neurons and is closely linked to glutamate-mediated neurotransmission. Nitric Oxide synthase is switched on only by glutamatergic receptors and appears to enhance the strength of glutamatergic input to monoaminergic neurons without requiring direct synaptic contact (Kiss and Vizi, 2001). 

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