Central neurotransmitter systems, metabolic

METABOLIC CONSEQUENCES OF MANIPULATING CENTRAL NEUROTRANSMITTER SYSTEMS... 

Adrenaline (epinephrine) is a catecholamine, which is released as a neurotransmitter from neurons in the central nervous system and as a hormone from chromaffin cells of the adrenal gland. Adrenaline is required for increased metabolic and cardiovascular demand during stress. Its cellular actions are mediated via plasma membrane bound G-protein-coupled receptors. 

It may come as a surprise that CO is synthesized by the human body and has roles in human metabolism. Specifically, an enzyme that degrades heme, a constituent of hemoglobin, our oxygen-transporting protein, makes CO, which is a neurotransmitter. Much more about neurotransmitters follows in chapter 21 when we talk about the central nervous system. For the present, just understand that specialized cells known as neurons are the conduits for communication in the nervous system. Neurotransmitters are small molecules that relay information from one neuron to another. Neurotransmitter CO is made, functions, and is quickly destroyed. Personally, I find it surprising that CO has such a critical role in the nervous system. Surprised or not, there it is and there is no doubt about it. 

Aspartic acid has a side chain carboxyl group that will lose a proton and become an anionic carboxylate group under physiological conditions. Aspartic acid is the metabolic precursor to gamma (y)-aminobutyric acid (GABA), an important inhibitory neurotransmitter in the human central nervous system. 

Some rather important indole derivatives influence our everyday lives. One of the most common ones is tryptophan, an indole-containing amino acid found in proteins (see Section 13.1). Only three of the protein amino acids are aromatic, the other two, phenylalanine and tyrosine being simple benzene systems (see Section 13.1). None of these aromatic amino acids is synthesized by animals and they must be obtained in the diet. Despite this, tryptophan is surprisingly central to animal metabolism. It is modified in the body by decarboxylation (see Box 15.3) and then hydroxylation to 5-hydroxytryptamine (5-HT, serotonin), which acts as a neurotransmitter in the central nervous system. 

Mechanism of Action An alcohol abuse deterrent that appears to interact with glutamate and gamma-aminobutyric acid neurotransmitter systems centrally, restoring their balance. Therapeutic Effect Reduces alcohol dependence. Pharmacokinetics Slowly absorbed from the G1 tract. Steady-state plasma concentrations are reached within 5 days. Does not undergo metabolism. Excreted in urine. Half-life 20-33 hr. 

Glutamate (Glu) is the most abundant amino acid in the central nervous system (CNS). It serves many functions as an intermediate in neuronal metabolism, e.g., as a precursor for GABA. About 30% of the total glutamate in the brain functions as the major excitatory neurotransmitter. 

None of the TCAs seem to have an effect on dopaminergic neurotransmission in the central nervous system (CNS). This has been supported by the lack of alterations in dopamine receptor sensitivity in chronically treated patients who have shown response to treatment (Sugrue, 1983). More recent investigations have also shown that administration of DMI to depressed subjects had no effect on levels of homovanillic acid, the principal metabolite of dopamine, in a measure of brain neurotransmitter production. In this investigation, DMI administration did increase norepinephrine production and overall cerebral metabolism (Lambert, 2000). 

Regulation of homocysteine metabolism appears to be especially important in the central nervous system, presumably because of the critical role of methyl transfer reactions in the production of neurotransmitters and other methylated products. It has been known for decades that mental retardation is a feature of the genetic diseases, such as CBS deficiency, that cause severe hyperhomocysteinemia and ho-mocystinuria. Impaired cognitive function is also seen in pernicious anemia, which causes hyperhomocysteinemia due to deficiency of cobalamin (see Chapter 28). Hyperhomocysteinemia also may be linked to depression, schizophrenia, multiple sclerosis, and Alzheimer s disease. The molecular mechanisms underlying these clinical associations have not yet been delineated. 

Central nervous system and neuromuscular junction. A remarkable number of alkaloids interfere with the metabolism and activity of neurotransmitters in the brain and nerve cells, a fact known to man for a thousand years (Table IV). The cellular interactions have been discussed above. Disturbance of neurotransmitter metabolism impairs sensory faculties, smell, vision, or hearing, or they may produce euphoric or hallucinogenic effects. 

This drug is a central nervous system stimulant that is considered to prevent the reuptake of norepinephrine and dopamine into the presynaptic neurones and increase the release of these neurotransmitters to the extraneuronal space. A high-fat meal increases its absorption. Methylphenidate in animal experiments was found to inhibit CYP1A and CYP2E1 by 50%. It is metabolized by de-esterification to inactive metabolites. 

The other characteristic feature of pellagra is the development of a depressive psychosis, superficially similar to schizophrenia and the organic psychoses, but clinically distinguishable by the sudden lucid phases that alternate with the most florid psychiatric signs. The mental symptoms may be the result of tryptophan depletion, and hence a lower availability of tryptophan for synthesis of the neurotransmitter serotonin (5-hydroxytryptophan). But the role of cADP-ribose and NAADP in controlling calcium release in response to neurotransmitters (Section 8.4.4) and impaired energy-yielding metabolism in the central nervous system as a result of depletion of NAD (P) may also be important. 

Observations of metabolic cross-correction provided the rationale for cellular replacement, achieved primarily through allogeneic hematopoietic stem cell or bone transplantation (HSCT) (Prasad and Kurtzberg, 2008). More recently, the use of neural stem cells (NSC) implanted in the brain of patients with late-infantile neuronal ceroid lipofuscinosis has been contemplated (Pierret et al., 2008) but there are no reports as yet of its potential efficacy. Within the central nervous system there must be proper integration of donor cells, and differentiation into appropriate cell types. As specialized cell types within the nervous system elaborate neurotransmitters and are involved with conducting electrical impulses, functional differentiation may be a major hurdle for the neurodegenerative LSDs. 

Serotonin and catecholamine functions in the central nervous system are both diverse and complex, and direct assessment of central neurotransmitters by cfinical laboratory methods is currently limited. The effects, however, of central serotonergic, dopaminergic, and serotonergic systems on metabolic and hormonal function are routinely measured in the clinical laboratory, and many of the therapeutic and illicit drugs that modulate central monoamine neurotransmission are monitored by laboratory techniques in a wide range of clinical settings. 

Central Nervous System. Dopamine monooxygenase (DMO) is an enzyme that requires copper, as a cofactor and uses ascorbate as an electron donor. This enzyme catalyzes the conversion of dopamine to norepinephrine, the important neurotransmitter. There are soluble and membrane-bound forms of the enzyme, the latter being found in the chromaffin granules of the adrenal cortex. Monoamine oxidase, one of the numerous amine oxidases, is a copper-containing enzyme that catalyzes the degradation of serotonin in the brain and is also involved in the metabolism of the catecholamines. 

Since iron is involved in many central nervous system processes that could affect infant behaviour and development, iron deficiency has adverse effects on brain development, both pre- and post-natal. In various epidemiological studies, it is reported that children with iron-deficiency anaemia have poorer performances on tests of some specific cognitive function. Animal experiments have identified some of the defects of reduced iron availability on brain function, which include post-translational changes (which result in a failure of iron incorporation into protein structures which are subsequently degraded), vulnerability of the developing hippocampus (with loss of the neuronal metabolic marker cytochrome c oxidase), and altered dendritic stmcture. Iron deficiency will also have a direct effect on myelin, including a decrease in myelin lipids and proteins, as well as neurotransmitter systems, since iron... 

Gietzen DW. 2000. Amino acid recognition in the central nervous system. Neural and Metabolic Control of Macro-nutrient Intake, Chapter 23. Berthoud HR, Seeley RJ, editors. New York CRC Press pp. 339-357. (Includes pharmacology of neurotransmitter signaling in the APC down-stream of AA sensing)... 

Hutson SM, Lieth E, La Noue KF. 2001. Function of leucine in excitatory neurotransmitter metabolism in the central nervous system. J Nutr 131 846S-850S. 

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