Monoamine neurotransmitters dopamine

Figure 13.7 Synthesis and structure of the trace amines phenylethylamine, /)-tyramine and tryptamine. These are all formed by decarboxylation rather than hydroxylation of the precursors of the established monoamine neurotransmitters, dopamine and 5-HT. (1) Decarboxylation by aromatic L-amino acid decarboxylase (2) phenylaline hydroxylase (3) tyrosine hydroxylase (4) tryptophan hydroxylase...

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... 

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... 

The biological basis of schizophrenia remains unknown. However, the monoamine neurotransmitter dopamine has played a key role in hypotheses about certain aspects of the five dimensions of symptoms in schizophrenia, discussed above. 

As noted in Chapter 3, stimulant drugs such as cocaine and the amphetamines are thought to affect the brain primarily through complex actions on monoamine neurotransmitters dopamine, norepinephrine, and serotonin. For example, both cocaine and the amphetamines block rcuptake of norepinephrine, serotonin, and particularly dopamine (Meyer 8c Quenzer, 2005). In addition, the amphetamines and methylphenidatc also increase the release of dopamine (Sulzer, Sonders, Poulsen, 8c Galli, 2005). Thus, the initial effect of stimulants is to produce a storm of activity in neural pathways that are sensitive to the monoamine transmitters. Because of this increased activity, however, and particularly because reuptake is blocked so that enzymes break down the neurotransmitters, the long-term effects of stimulant use involve depletion of monoamines. If you remember that low levels of monoamines are linked to clinical depression (see Chapter 3), tlien you have the basis for one theory of why the aftereffects of heavy cocaine use involve depression (Dackis 8c Gold, 1985). To explain this hypothesis, we must turn briefly to data from the animal laboratory. 

Acute treatment with nonselective MAO inhibitors (iproniazid, tranylcypromine, phenelzine), as a consequence of inhibiting both forms of the enzyme, increase, brain levels of all monoamines (phenylethylamine, tryptamine, methylhistamine aminergic neurotransmitters (dopamine, noradr enaline, adrenaline and serotonin). By contrast MAO-A inhibitors (clorgyline) increase serotonin and noradrenaline, while MAO-B inhibitors (selegiline, rasagiline) increase brain levels... 

The transporters for 5HT, noradrenaline and dopamine, biogenic monoamines, are genetically related, exist as single isoforms and are expressed on the surface of nerve cells, which use monoamines as (or convert them into) their cognate neurotransmitter. The single-isoform monoamine transporters fulfil all three fundamental functions (reuptake, limiting synaptic transmission, and control of the extracellular neurotransmitter concentration). Inactivation of DAT, NET, or SERT results in an increased extracellular lifetime and level of monoamine neurotransmitter, but decreased intracellular storage and evoked release (Fig. 3). 

Cocaine and desipramine inhibit the reuptake of monoamine neurotransmitters whereas amphetamine, which is a phenylalkylamine - similar in structure to the catecholamines, see Fig. 4 - competes for uptake and more importantly, evokes efflux of the monoamine neurotransmitters. All of them exert antidepressant effects. Cocaine and amphetamine are addictive whereas tricyclic antidepressants and their modern successors are not. The corollaty of the addictive properties is interference with DAT activity. Blockade of DAT by cocaine or efflux elicited by amphetamine produces a psychostimulant effect despite the different mechanisms even the experienced individual can hardly discern their actions. Because of the risk associated with inhibiting DAT mediated dopamine clearance the antidepressant effects of psychostimulants has not been exploited. 

The patty drug MDMA (3,4-methylene-dioxymetham-phetamine) as well as amphetamine causes efflux of all monoamine neurotransmitters. The effects of MDMA are described as psychostimulant and hallucinogenic and are judged differently from those of amphetamine. This difference is due to the stronger inhibition of SERT by MDMA as compared with amphetamine, which is a more potent dopamine releaser and moreaddictivethan MDMA. 

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. 

The synthesis and metabolism of trace amines and monoamine neurotransmitters largely overlap [1]. The trace amines PEA, TYR and TRP are synthesized in neurons by decarboxylation of precursor amino acids through the enzyme aromatic amino acid decarboxylase (AADC). OCT is derived from TYR. by involvement of the enzyme dopamine (3-hydroxylase (Fig. 1 DBH). The catabolism of trace amines occurs in both glia and neurons and is predominantly mediated by monoamine oxidases (MAO-A and -B). While TYR., TRP and OCT show approximately equal affinities toward MAO-A and MAO-B, PEA serves as preferred substrate for MAO-B. The metabolites phenylacetic acid (PEA), hydroxyphenylacetic acid (TYR.), hydroxymandelic acid (OCT), and indole-3-acetic (TRP) are believed to be pharmacologically inactive. 

The amphetamine-like properties of trace amines are best described for PEA which shares close structural similarity to amphetamine and can displace monoamine neurotransmitters from synaptic vesicles and trigger their release into the synaptic cleft by acting on the dopamine transporter. However, this effect is only observed at high, supra-physiological PEA concentrations and thus might not occur under physiological conditions. 

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. 

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... 

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. 

Many monoamine neurotransmitters are now thought to work by this receptor-linked second messenger system. In some cases, however, stimulation of the posts)maptic receptors can cause the inhibition of adenylate cyclase activity. For example, D2 dopamine receptors inhibit, while receptors stimulate, the activity of the cyclase. 

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. 

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. 

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. 

Dopamine—A monoamine neurotransmitter formed in the brain and essential for the normal functioning of the central nervous system. 

Stimulants have chemical structures that are similar to key brain neurotransmitters called monoamines, including dopamine and norepinephrine. Their therapeutic effect is achieved by slow and steady increases of dopamine that are similar to the natural production of this chemical by the brain. The doses prescribed by physicians start low and increase gradually until a therapeutic effect is reached. However, when taken in doses and routes other than those prescribed, stimulants can increase the brain s dopamine levels in a rapid and highly amplified manner—as do most other drugs... 

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). 

Noradrenergic neurons. The noradrenergic neuron uses NE for its neurotransmitter. Monoamine neurotransmitters are synthesized by means of enzymes, which assemble neurotransmitters in the cell body or nerve terminal. For the noradrenergic neuron, this process starts with tyrosine, the amino acid precursor of NE, which is transported into the nervous system from the blood by means of an active transport pump (Fig. 5 — 17). Once inside the neuron, the tyrosine is acted on by three enzymes in sequence, the first of which is tyrosine hydroxylase (TOH), the rate-limiting and most important enzyme in the regulation of NE synthesis. Tyrosine hydroxylase converts the amino acid tyrosine into dihydroxyphenylalanine (DOPA). The second enzyme DOPA decarboxylase (DDC), then acts, converting DOPA into dopamine (DA), which itself is a neurotransmitter in some neurons. However, for NE neurons, DA is just a precursor of NE. In fact, the third and final NE synthetic enzyme, dopamine beta-hydroxylase (DBH), converts DA into NE. The NE is then stored in synaptic packages called vesicles until released by a nerve impulse (Fig. 5—17). 

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. 

Major depression has been classically explained by deficiences in the monoamine neurotransmitters 5-HT, noradrenaline, and dopamine. The importance of these monoamine systems for the vulnerablity to depression has recently been confirmed (Ruhe et al. 2007). Do presynaptic 5-HTib autoreceptors play any role Two groups of findings tend to answer this question in the affirmative. The depression-like state... 

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