Brain norepinephrine distribution

Norepinephrine is made in cells located in the brain stem, mostly in a group of cells called the locus coeruleus. These neurons send widespread projections throughout the brain. This distribution has functional consequences. Small disturbances in the locus coeruleus can have a large impact on many different brain areas at the same time, and thus influence many behaviors. Disorders of emotion and mood are similar in that they simultaneously impact many different behaviors. Therefore, it is reasonable to suggest that norepinephrine might affect emotion in some ways. 

The endogenous release of the potent vasoconstrictor neuropeptide Y (NPY) is increased during sepsis and the highest levels are detected in patients with shock (A8). NPY is a 36-amino-acid peptide belonging to the pancreatic polypeptide family of neuroendocrine peptides (T2). It is one of the most abundant peptides present in the brain and is widely expressed by neurons in the central and peripheral nervous systems as well as the adrenal medulla (A3). NPY coexists with norepinephrine in peripheral sympathetic nerves and is released together with norepinephrine (LI9, W14). NPY causes direct vasoconstriction of cerebral, coronary, and mesenteric arteries and also potentiates norepinephrine-induced vasoconstriction in these arterial beds (T8). It appears that vasoconstriction caused by NPY does not counterbalance the vasodilatator effects of substance P in patients with sepsis. The properties of vasodilatation and smooth muscle contraction of substance P are well known (14), but because of the morphological distribution and the neuroendocrine effects a possible stress hormone function for substance P was also advocated (J7). Substance P, which is a potent vasodilatator agent and has an innervation pathway similar to that of NPY, shows a low plasma concentration in septic patients with and without shock (A8). 

The action of catecholamines released at the synapse is modulated by diffusion and reuptake into presynaptic nerve terminals. Catecholamines diffuse from the site of release, interact with receptors and are transported back into the nerve terminal. Some of the catecholamine molecules may be catabolized by MAO and COMT. The cate-cholamine-reuptake process was originally described by Axelrod [18]. He observed that, when radioactive norepinephrine was injected intravenously, it accumulated in tissues in direct proportion to the density of the sympathetic innervation in the tissue. The amine taken up into the tissues was protected from catabolic degradation, and studies of the subcellular distribution of catecholamines showed that they were localized to synaptic vesicles. Ablation of the sympathetic input to organs abolished the ability of vesicles to accumulate and store radioactive norepinephrine. Subsequent studies demonstrated that this Na+- and Cl -dependent uptake process is a characteristic feature of catecholamine-containing neurons in both the periphery and the brain (Table 12-2). 

The biogenic amines are the preferred substrates of MAO. The enzyme comes in two flavors, MAO-A and MAO-B, both of which, like FMO, rely on the redox properties of FAD for their oxidative machinery. The two isoforms share a sequence homology of approximately 70% (81) and are found in the outer mitochondrial membrane, but they differ in substrate selectivity and tissue distribution. In mammalian tissues MAO-A is located primarily in the placenta, gut, and liver, while MAO-B is predominant in the brain, liver, and platelets. MAO-A is selective for serotonin and norepinephrine and is selectively inhibited by the mechanism-based inhibitor clorgyline (82). MAO-B is selective for /1-phcncthylaminc and tryptamine, and it is selectively inhibited by the mechanism-based inhibitors, deprenyl and pargyline (82) (Fig. 4.32). Recently, both MAO-A (83) and MAO-B (84) were structurally characterized by x-ray crystallography. 

Norepinephrine is widely distributed throughout brain in a nonuniform pattern, discrete from that of other amine systems such as dopamine and serotonin, although overlapping in several areas. The majority of noradrenergic axons and nerve endings found in the brain originate from the locus co-eruleus, a small, well-delineated cluster of cell bodies located in the pontine brain stem, just below the floor of the fourth ventricle. Given the wide distribution of norepinephrine in the brain [widely documented in the psychiatric literature), remarkably few neurons, estimated as 12,000 neurons on each... 

MAOIs act by mitigating the actions of monoamine oxidase in the neuron and increasing monoamine content. There are two forms of monoamine oxidase. MAO-A is present in both dopamine and norepinephrine neurons and is found primarily in the brain, gut, placenta, and liver its primary substrates are norepinephrine, epinephrine, and serotonin. MAO-B is found primarily in serotonergic and histaminergic neurons and is distributed in the brain, liver, and platelets. MAO-B acts primarily on tyramine, phenylethylamine, and benzylamine. Both MAO-A and -B metabolize tryptamine and dopamine. 

Thus, virtually all side effects of the selective NRIs can be understood as undesirable actions of norepinephrine in undesirable pathways at undesirable receptor subtypes. Just as for the SSRls, this occurs because it is not possible for a systemically administered drug to act only at the desirable receptors in the desirable places it must act everywhere it is distributed, which means all over the brain and all over the body. Fortunately, selective NRI side effects are more of a nuisance than a danger, and they generally attenuate over time, although they can cause an important subset of p>atients to discontinue treatment. 

In addition to P-endorphin, P-LPH contains the amino acid sequence of another endogenous opioid, met-enkephalin. However, this peptide is not the product of P-LPH breakdown, but rather arises from a precursor molecule loiown as pro-enkephalin. Pro-enkephalin is widely distributed in neurons throughout the brain and spinal cord. Some pro-enkephalin is found in the pituitary gland, but most is localized in the catecholamine-synthesizing cells of the adrenal medulla and is co-released with epinephrine and norepinephrine. In the medulla, pro-enkephalin gives rise to met-enkephalin (Tyr-Gle-Gle-Phe-Met) and leu-enkephalin (Tyr-Gle-Gle-Phe-Leu) and to larger opioid peptides. A third family of endogenous opioid peptides is derived from prodynorphin, a prohormone stored primarily in the poste-... 

NE Innervation Pattern and Receptor Distribution A significant modulatory input to the MOB is from the pontine nucleus, locus coeruleus (LC). In the rat, all LC neurons contain the neurotransmitter, norepinephrine (NE) LC contains the largest population of NE neurons in the brain. It has been estimated that up to 40% of LC neurons (400-600 of a total of 1,600 LC neurons) project to the bulb in the rat (Shipley et al., 1985). A subset of LC neurons projecting to MOB contain NPY (Bouna et al., 1994). NE fibers terminate in MOB with laminar specificity. LC axons project mainly to the subglomerular layers of the bulb, particularly the IPL and GCL (McLean et al., 1989). The EPL and MCL are moderately innervated, whereas the GL is nearly devoid of NE input. 

Kuhar M. J., Shaskan, E. G. and Snyder, S. H. (1971) The subcellular distribution of endogenous and exogenous serotonin in brain tissue comparison of synaptosomes storing serotonin, norepinephrine and y-aminobutyric acid. J. Neurochem., 18 333-343. 

Desipramine is a tricyclic antidepressant, inhibits reuptake of norepinephrine and serotonin in CNS, and is indicated in relief of symptoms of depression. Desipramine (75 to 150 mg p.o./day in divided doses) is indicated in endogenous depression major depression with melancholia or psychotic symptoms depression associated with organic brain disease, alcoholism, schizophrenia, or mental retardation and the depressive phase of manic-depressive disorder. Desipramine is absorbed rapidly from the GI tract, distributed widely in the body, and appears also in breast miUc. It is bound to plasma proteins to the extent of 90%, undergoes extensive first-pass metabolism, and its metabolites are excreted in urine. Desipramine strongly blocks the norepinephrine uptake mechanism and has no effect on the uptake of serotonin. Desipramine has weak alpha -adrenergic and... 

Monoamine oxidase (MAO) is an enzyme present in the outer mitochondrial membrane of neuronal and non-neuronal cells. Two isoforms of MAO exist MAO-A and MAO-B. The MAO enzymes are responsible for the oxidative deamination of endogenous and xenobiotic amines, and have different substrate preferences, inhibitor specificities, and tissue distributions. MAO inhibition allows endogenous and exogenous substrates to accumulate, and may thereby alter the dynamics of regular monoamine transmitters, such as norepinephrine, serotonin, and dopamine. Specifically, MAO-A deaminates serotonin, norepinephrine, and dopamine, and MAO-B deaminates dopamine, [3-phenylethylamine, and benzylamine. In the human brain, about 75% of MAO is of the B subtype. Hence, the primary effect of MAO inhibitors (MAOIs) is to increase the availability of these neurotransmitters at the nerve terminal. 

The enzyme L-aromatic amino acid decarboxylase (AADC, EC 4.1.1.28) lacks substrate specificity and has been considered to be involved in the formation of the catecholamines and serotonin. There are many differences in the optimal conditions for enzyme activity, including kinetics, affinity for PLP, activation and inhibition by specific chemicals, and regional differences in the distribution of DOPA and 5-HTP decarboxylation activities. Nonparallel changes in brain monoamines in the vitamin Bg-deficient rat have been reported (7-9). Brain content of dopamine and norepinephrine were not decreased during deficiency, whereas serotonin was significantly decreased. 

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