Monoamines norepinephrine serotonin

Impulse traffic in the neo- and pa-leospinothalamic pathways is subject to modulation by descending projections that originate from the reticular formation and terminate at second-order neurons, at their synapses with first-order neurons, or at spinal segmental interneurons (descending antinociceptive system). This system can inhibit impulse transmission from first- to second-order neurons via release of opio-peptides (enkephalins) or monoamines (norepinephrine, serotonin). 

Listing of antidepressants grouped by principal mechanism of action in the synapse. Abbreviations MAOI—irreversible = irreversible monoamine oxidase inhibitor MAOI—reversible = reversible monoamine oxidase inhibitor NDRl = norepinephrine/ dopamine reuptake inhibitor NRI = norepinephrine reuptake inhibitor NSRl = norepinephrine/serotonin reuptake inhibitor NSSA = norepinephrine/specific serotonin agonist SRI = serotonin reuptake inhibitor SRl/serotonin-2 blocker = serotonin reuptake inhibitor and serotonin-2 receptor antagonist. 

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. 

Monoamine oxidases (MAOs) are mitochondrial membrane enzymes. These flavin-dependent enzymes are responsible for the oxidative deamination of numerous endogenic and exogenic amines (norepinephrine, serotonin, dopamine, etc.). MAO A and B take part in the regulation of these amines in many organs, such as the brain. The essential physiological role of these amines, especially in the central nervous system, has motivated the search for inhibitors of their catabolism in order to enhance the synaptic concentration of neuroamines. 

Mechanism of Action An MAOI that inhibits the activity of the enzyme monoamine oxidase at CNS storage sites, leading to increased levels of the neurotransmitters epinephrine, norepinephrine, serotonin, and dopamine at neuronal receptor sites. Therapeutic Effect Relieves depression. 

The monoamine hypothesis of depression develops from the finding that drugs reducing monoamine neurotransmission cause depression. Monoamines include serotonin, norepinephrine, and dopamine. 

TABLE 15-1B. Compounds marketed since 1990 or under development as selective or combination norepinephrine/serotonin uptake inhibitors or selective monoamine oxidase inhibitors [MAOIs]... 

Of the clinically tested new antipsychotics, ziprasidone has the highest 5-HT2A/D2 receptor-affinity ratio. Ziprasidone is an antagonist at the a -adrenoreceptor, but its affinity is half that of its D 2 affinity. In addition, compared with its affinity for D 2 and 5-HT2A receptors, ziprasidone has a relatively low affinity for histamine receptors (pKJ = 7.33). In vitro, ziprasidone is a moderately potent inhibitor of neuronal reuptake of norepinephrine, serotonin, and, to a lesser extent, dopamine. This property is shared with some antidepressants, and contrasts with risperidone, which is inactive at all three monoamine uptake sites. 

Pharmacologic targeting of monoamine transporters. Commonly used drugs such as antidepressants, amphetamines, and cocaine target monoamine (norepinephrine, dopamine and serotonin) transporters with different potencies. A shows the mechanism of reuptake of norepinephrine (NE) back into the noradrenergic neuron via the norepinephrine transporter (NET), where a proportion is sequestered in presynaptic vesicles through the vesicular monoamine transporter (VMAT). and C show the effects of amphetamine and cocaine on these pathways. See text for details. 

Neuronal systems that contain one of the monoamines—norepinephrine, dopamine, or 5-hydroxytryptamine (serotonin)— provide examples in this category. Certain other pathways emanating from the reticular formation and possibly some peptide-containing pathways also fall into this category. These systems differ in fundamental ways from the hierarchical systems, and the noradrenergic systems serve to illustrate the differences. 

An example of a class of drugs that interrupt neurotransmitter degradation is the monoamine oxidase (MAO) inhibitors. MAO is a mitochondrial enzyme that exists in two forms (A and B). Its major role is to oxidize monoamines such as norepinephrine, serotonin, and dopamine by removing the amine grouping from the neurotransmitters. Under normal circumstances, MAO acts as a safety valve to degrade any excess transmitter molecules that may spill out of synaptic vesicles when the neuron is in a resting state. MAO inhibitors prevent this inactivation. In their presence, any neurotransmitter molecules that leak out of the synaptic vesicles survive to enter the synapse intact. Receptors are thus exposed to a greater amount of the neurotransmitter. 

In the 1960s researchers formulated, and later refined, the so-called monoamine hypothesis of depression. This hypothesis states that symptoms of depression are due to alterations in the functioning of certain neurotransmitters known as monoamines, notably norepinephrine, serotonin, and to a lesser degree, dopamine. Roles for other neurotransmitters have been identified in recent years. The foundation of this hypothesis rests on the finding that all antidepressant medications known at the time had, to some extent, the ability to increase the availability of these neurotransmitters at the synaptic level. Patients and the general public often refer to this hypothesis as chemical imbalance. ... 

These were the first type of antidepressant used. Neurotransmitters (e.g. norepinephrine, serotonin and dopamine) are generally monoamines that, when released, are either reabsorbed into the proximal nerve and metabolized by MAO or destroyed by catechol-O-methyl transferase in the synaptic cleft. 

Irreversibly blocks monoamine oxidase (MAO) from breaking down norepinephrine, serotonin, and dopamine... 

Catecholamine—Monoamines such as the neurotransmitters norepinephrine, serotonin, and dopamine that are synthesized from the amino acid, tyrosine, and have similar structures. Conditioned reflex—response in which one stimulus, the conditioned one, is associated with and elicits the same response as another stimulus, the unconditioned stimulus. 

Possibly the best evidence suggesting involvement of norepinephrine and serotonin in major depressive disorder devolved from depletion studies (Delgado et al., 1990). In these stndies, patients who have responded to treatment for depression are given procedures, which deplete brain levels of serotonin or norepinephrine. Serotonin levels are decreased by nse of a low monoamine diet, followed by a drink which inclndes all the amino acids except the serotonin precnrsor tryptophan. Norepinephrine levels are depleted by administration of alpha-methylparatyrosine. In patients who had responded to treatment with a serotonergic antidepressant, depletion of serotonin cansed a prompt and dramatic, but brief reoccurrence of the symptoms of major depression. In patients who had responded to treatment with a noradrenergic antidepressant, depletion of norepinephrine caused a relapse into depression. The converse was not true in other words, serotonin depletion did not canse relapse in patients who responded to noradrenergic antidepressants, and vice versa. 

The antidepressants, generally, produce their therapeutic effects by blocking the reuptake of one or more catecholamines (norepinephrine, serotonin, and dopamine), which leads to a decrease (down-regulation) of the number of post-synaptic receptors—generally within seven to twenty-one days, coinciding with the onset of clinical effect (see chapter 3). The MAOIs block monoamine oxidase, which metabolizes the catecholamines stored at the nerve ending of the presynaptic neuron—thereby making more catecholamine available. Stimulants increase the release of catecholamines. Buspirone is a 5-HT lA receptor blocker. 

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. 

The effects of amphetamines are due to the increase of neurotransmitters norepinephrine, serotonin, and dopamine in central synapses. This increase is from increased release and reuptake blockade of catecholamines. Amphetamines may also inhibit monoamine oxidase. These mechanisms combine to produce the sympathomimetic and central nervous system (CNS) effects seen with amphetamine abuse. 

With respect to the role of the brain monoamines in mental depression, it may be stated that all of the antidepressant drugs described in this section are capable of increasing brain levels of norepinephrine, Serotonin, and dopamine. Recent work by Spector (103) would seem to indicate that norepinephrine may be the critical neurohormone which mediates the effects of the MAO inhibitors, inasmuch as pargyline was incapable of counteracting the depressant effects of reserpine (even in the presence of significant amounts of Serotonin and dopamine) until there was a small but definite rise in norepinephrine levels. This work was done in rabbits which had previously been depleted of brain monoamines by the administration of reserpine. 

Monoamine oxidase, which can destroy a number of amines, including norepinephrine, serotonin, and others, can affect the relative level of these amines in the brain. Therefore, in some cases where these are apparently at a low level, individuals may be treated with a drug, or a family of drugs, that are monoamine oxidase inhibitors. In a number of cases, these drugs bring about a restitution of normal mental functions. However, individuals on these... 

Monoamine oxidase (MAO) is another flavoenzyme that catalyzes the oxidation of carbon-nitrogen bonds. MAO has been studied extensively due to its physiological importance in the catabolism of amine neurotransmitters, such as norepinephrine, serotonin, and dopamine. There are two isozymes, MAO A and MAO B. The roles of both MAO A and MAO B are well documented in age-dependent neurodegenerative diseases and MAO inhibitors have been used to treat Parkinson s disease and depression. ... 

Isocarboxazid is an MAO inhibitor, which blocks activity of enzyme MAO, thereby increasing monoamine (e.g., epinephrine, norepinephrine, serotonin) concentrations in CNS. It is indicated in the treatment of depression. Isocarboxazid (30 mg/kg) is a monoamine oxidase inhibitor (MAO) indicated for the treatment of depressed patients who have become refractory to tricyclic antidepressants... 

It was initially believed that the antidepressant effectiveness of MAOIs was the direct result of MAO inhibition. This acute effect decreases degradation of monoamines (e.g., norepinephrine, serotonin, or dopamine) stored in presynaptic neurons, thereby resulting in an increased amount of these neurotransmitters available at the synapse. More recent research indicates that this model does not fully explain the mechanism of MAOIs efficacy. For example, the positive (h-) stereoisomer of tranylcypromine is a poor antidepressant despite inhibiting MAO. The main pharmacologic difference between the negative (-) and + isomers of tranylcypromine is that the former has much weaker effects as a norepinephrine reuptake inhibitor in relation to its potency as an MAOI. The other MAOIs may also block the reuptake of selected neurotransmitters. However, like the non-MAOI uptake inhibitors, these acute effects often precede clinical antidepressant effects by weeks. More consistent with the 2- to 4-week lag in therapeutic effect, chronic treatment with a diverse number of MAOIs has been shown to reduce the number of a2- and P-adrenergic and serotonin (5-HT2) postsynaptic binding sites in the brain. 

A combined extraction system for the selective and quantitative isolation of the monoamines norepinephrine, epinephrine, dopamine, serotonin and their metabolites... 

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. 

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