Monoamine neurotransmitters serotonin

Pyridoxine (vitamin Bg, 18) (Fig. 13) assists in the balancing of sodium and potassium as well as promoting red blood cell production. A lack of pyridoxine can cause anemia, nerve damage, seizures, skin problems, and sores in the mouth. It is required for the production of the monoamine neurotransmitters serotonin, dopamine, norepinephrine, and epinephrine, as it is the precursor to pyridoxal phosphate, which is the cofactor for the aromatic amino acid decarboxylase enzyme. 

Another major focus of interest for the investigation of anxiety disorders is the monoamine neurotransmitter serotonin (5-HT see also chapter by Mohler et al., this volume) because of reduced levels of 5-HT receptors found in patients... 

Aggressive behavior is related to the monoamine neurotransmitters serotonin, dopamine, and noradrenaline. The enzymes monoamine oxidase (MAO) A and B play roles in the metabolism of catecholamines in the brain and peripheral tissues. MAOA degrades dopamine, serotonin, and noradrenaline. 

Major depressive disorder is among the most common psychiatric disorders in the U.S. with an estimated prevalence of about 10% in the general population [49]. The effects of antidepressants can be linked to the improvement of neurotransmission by the monoamine neurotransmitters, serotonin, norepinephrine, and dopamine [50]. 

Trace amines are a family of endogenous monoamine compounds including (3-phenylethylamine (PEA), p-tyramine (TYR), tryptamine (TRP) and octopamine (OCT). The trace amines share close structural similarity with the well known classical monoamine neurotransmitters such as dopamine (DA), norepinephrine (NE) and serotonin (5-HT). As their name suggests, trace amines occur in comparably much lower abundance than monoamine neurotransmitters. For historical reasons, other endogenous amine compounds which might share some structural similarities with PEA, TYR, TRP or OCT are not referred to as trace amines. 

O Classic views as to the cause of major depressive disorder focus on the monoamine neurotransmitters norepinephrine (NE), serotonin (5-HT), and to a lesser extent, dopamine (DA) in terms of both synaptic concentrations and receptor functioning. 

Altered removal of a neurotransmitter from the synaptic cleft. The third mechanism by which drugs may alter synaptic activity involves changes in neurotransmitter reuptake or degradation. A very well known example of a drug in this category is Prozac (fluoxetine), which is used to treat depression. The complete etiology is unknown, but it is widely accepted that depression involves a deficiency of monoamine neurotransmitters (e.g., norepinephrine and serotonin) in the CNS. Prozac, a selective serotonin reuptake inhibitor, prevents removal of serotonin from the synaptic cleft. As a result, the concentration and activity of serotonin are enhanced. 

Neurochemical theories for the affective disorders propose that there is a link between dysfunctional monoaminergic synapses within the central nervous system (CNS) and mood problems. The original focus was the neurotransmitter noradrenaline, or NA (note noradrenaline is called norepinephrine, or NE, in American texts). Schildkraut (1965) suggested that depression was associated with an absolute or relative deficiency of NA, while mania was associated with a functional excess of NA. Subsequently, another monoamine neurotransmitter 5-hydroxytryptamine (5-HT), or serotonin, was put forward in a rival indoleamine theory (Chapter 2). However, it was soon recognised that both proposals could be reconciled with the available clinical biochemical and pharmacological evidence (Luchins, 1976 Green and Costain, 1979). 

Transporters for dopamine (DAT), serotonin (SERT) and norepinephrine (NET) are the initial targets for psychomotor stimulants. By interacting with these transporters (Chs 12 and 13), psychomotor stimulants increase extracellular levels of monoamine neurotransmitters. Cocaine is a monoamine uptake inhibitor. The reinforcing effects of cocaine correlate best with its binding potency at the DAT. However, experiments with monoamine transporter-deficient mice suggest that cocaine actions at... 

Monoamine The primary psychoactive mechanism of cocaine is blocking reuptake of the monoamine neurotransmitters dopamine, norepinephrine, and serotonin, leading to increased available synaptic transmitters (O Brien 1996). Chronic use is associated with changes in... 

This conclusion is supported by the mechaiusm of action of imipramine. Once a neurotransmitter has been released into the synapse, there are two ways to terminate its action. The first is to degrade it to inactive products, by MAO for example. The second is to remove the neurotransmitter through reuptake into the presynaptic neuron. This mechaiusm is the predominant one for clearing the synapse of serotonin, norepinephrine, and dopamine. Specific proteins embedded in the neuronal plasma membrane mediate the reuptake of these monoamine neurotransmitters. Imipramine is a nonspecific monoamine reuptake inhibitor that is, it slows the reuptake of aU three of these monoamines, which enhances the activity of these neurotransmitters. This also suggests that a deficit in the activity of one or more of the monoamines underlies the problem of depression. 

The pathways for synthesis of the monoamine neurotransmitters are not, at least in some neurones, saturated with precursor amino acids (tyrosine for formation of noradrenaline plus dopamine tryptophan for formation of 5-hydroxytryptamine (serotonin)). Marked increases in the blood level of these amino acids can increase their concentrations in neurones which can influence the concentration of the respective neurotransmitters in some neurones in the brain. This may result in changes in behaviour. 

From L-tryptophan, the serotonin synthesis pathway also begins. Serotonin is 5-hydroxytryptamine. It is derived from L-tryptophan, which at first is simply hydroxylated to 5-hydroxy-L-tryptophan, and subsequently to the serotonin (Figure 39). Structurally, serotonin is also a 5-HT monoamine neurotransmitter. 

The transmethylation hypothesis depended on the psychosis of mescaline as an example of how methylated compounds similar in structure to the monoamine neurotransmitters could be psychotogenic, and demonstrated how methionine, the precursor of the methyl donor S-adenosylmethionine, could exacerbate the psychotic symptoms of schizophrenia in patients. This theory was fed by studies of the now notorious pink spot, an amine found in paper chromatography of urine extracts from schizophrenics and thought to be 3,4-dimethoxyphenylethylamine (i.e., O-methylated dopamine). Subsequent studies eventually identified this as another compound or compounds, primarily of dietary origin. Another methylated derivative erroneously proposed to be found in higher quantities in schizophrenia was dimethyltryptamine. This compound is similar in structure to LSD, the hallucinogenic nature of which was the key to the serotonin deficiency hypothesis, which proposed that the known antagonism of serotonin (5-HT) by LSD indicated that psychotic disorders such as schizophrenia may result from a hypofunction of 5-HT. 

Ultimately, the effects of virtually aU existing antidepressants can be traced to the improvement of neurotransmission in the brain by one or more monoamine neurotransmitters, that is serotonin (5-HT, 4), norepinephrine (NE, 5), and dopamine (DA, 6). By blocking monoamine transporters, which remove the neurotransmitter from the synapse and extracellular space by uptake processes, the drugs increase extracellular levels of the transmitter and cause a cascade of intracellular events leading to the desired CNS effect. 

About the same time as the reserpine finding, physicians noticed that some of the drugs used to treat other diseases appeared to have a beneficial side effect—raising the patient s mood. Upon further testing, a chemically modified version of one of these drugs effectively reduced the symptoms of depressed patients. This drug, iproniazid, inhibits MAO, the enzyme that destroys the monoamine neurotransmitters— dopamine, norepinephrine, and serotonin. As a result, more of these... 

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. 

The first major theory about the biological etiology of depression hypothesized that depression was due to a deficiency of monoamine neurotransmitters, notably norepinephrine (NE) and serotonin (5-hydroxytryptamine [5HT]) (Figs. 5 — 13 through... 

In order to understand the monoamine hypothesis, it is necessary first to understand the normal physiological functioning of monoaminergic neurons. The principal monoamine neurotransmitters in the brain are the catecholamines norepinephrine (NE, also called noradrenaline) and dopamine (DA) and the indoleamine serotonin (5HT). 

Glutamate removal. Glutamate s actions ate stopped not by enzymatic breakdown, as in other neurotransmitter systems, but by removal by two transport pumps. The first of these pumps is a presynaptic glutamate transporter, which works as do all the other neurotransmitter transporters already discussed for monoamine neurotransmitter systems such as dopamine, norepinephrine, and serotonin. The second transport pump, located on nearby glia, removes glutamate from the synapse and terminates its actions there. Glutamate removal is summarized in Figure 10—22. 

Fig. 1. Occurrence of H3 receptors inhibiting release of acetylcholine, of amino acid and monoamine neurotransmitters in the mammalian CNS in vitro. The schematic drawing represents a midsagittal section of the human brain three areas with a more lateral position are shown by broken line (substantia nigra and part of the hippocampus and of the striatum). For each of the six regions of the CNS (subregions given in brackets), in which H3 heteroreceptors have been identified, the neurotransmitter(s) and the species are indicated. The superscripts refer to the numbers of the papers as listed under References. Own unpublished data suggest that an H3 receptor-mediated inhibition of noradrenaline release also occurs in the human cerebral cortex and hippocampus and in the guinea-pig cerebral cortex. Note that a presynaptic location has not been verified for each of the H3 heteroreceptors or has been even excluded (for details, see Table 1). Abbreviations ACh, acetylcholine DA, dopamine GABA, y-aminobutyric acid Glu, glutamate 5-HT, 5-hydroxytryptamine, serotonin NA, noradrenaline...

Monoamine oxidase (ABBR MAO) An enzyme that breaks down monoamine neurotransmitters such as dopamine, norepinephrine, and serotonin. 

Monoamine Release and Uptake Tacrine has been shown to induce monoamine release and to inhibit monoamine uptake, leading to an increase in several monoamine neurotransmitters including dopamine, serotonin, and norepinephrine. 

In addition to the cholinergic deficit, Alzheimer s disease has also been shown to be characterized by marked deficits in the monoamine neurotransmitters norepinephrine and serotonin, as well as in glutamate and some neuropeptide neurotransmitters (Figure 27.6). 

Primary amines are oxidized in the body by monoamine oxidase (MAO). MAO converts the amine to an imine, which is hydrolyzed to yield an aldehyde and ammonia. One function of MAO is to regulate the levels of the neurotransmitters serotonin and norepinephrine. Monoamine oxidase inhibitors prevent the oxidation (and inactivation) of these neurotransmitters, thereby elevating mood. MAO inhibitors were the first antidepressants, but they are used sparingly now because of numerous side effects. 

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