Monoamines synthesis

Methylphenidate like cocaine largely acts by blocking reuptake of monoamines into the presynaptic terminal. Methylphenidate administration produces an increase in the steady-state (tonic) levels of monoamines within the synaptic cleft. Thus, DAT inhibitors, such as methylphenidate, increase extracellular levels of monoamines. In contrast, they decrease the concentrations of the monoamine metabolites that depend upon monoamine oxidase (MAO), that is, HVA, but not catecholamine-o-methyltransferase (COMT), because reuptake by the transporter is required for the formation of these metabolites. By stimulating presynaptic autoreceptors, methylphenidate induced increase in dopamine transmission can also reduce monoamine synthesis, inhibit monoamine neuron firing and reduce subsequent phasic dopamine release. 

Kehr, W., and Speckenbach, W. (1978) Effect of lisuride and LSD on monoamine synthesis after axotomy or reserpine treatment in rat brain. Naunyn Schmiedebergs Arch. Pharmacol., 301 163-169. 

Lassen, J. B. (1974) The effect of p-chloroamphetamine on motility in rats after inhibition of monoamine synthesis, storage, uptake, and receptor interaction. Psychopharmacologia, 34 243-254. 

The most common reason for the underutilization of MAOIs is the potential for serious consequences of MAOI drug-food and drug-drug interactions. Combined MAOI treatment with (1) foods or medications involved in monoamine synthesis (2) monoamines themselves or (3) other sympathomimetics routinely found in over-the-counter medications can result in hy-peradrenergic crises or serotonin toxicity (Blackwell, 1991). 

When presynaptic neurons use monoamine neurotransmitters, they manufacture not only the monoamine neurotransmitters themselves but also the enzymes for monoamine synthesis (Fig. 1—7), the receptors for monoamine reuptake and regulation (Fig. 1—8) and the synaptic vesicles loaded with monoamine neurotransmitter. They do this on receiving instructions from the "command center or headquarters, namely the cell nucleus containing the neuron s deoxy-ribonucleic acid (DNA). These activities occur in the cell body of the neuron, but then monoamine presynaptic neurons send all of these items to the presynaptic nerve terminals, which act as field offices for that neuron throughout the brain (Figs. 1—1 to 1—3, 1—7, 1—8). Neurotransmitter is thus packaged and stored in the presynaptic neuron in vesicles, like a loaded gun ready to fire. 

Pani, A.K. and Croll, R.P. (1998) Pharmacological analysis of monoamine synthesis and catabolism in the scallop, Placopecten magellanicus. Gen. Pharmacol., 31, 67-73. 

Fernstrom, J. D., Aromatic amino acids and monoamine synthesis in the central nervous system Influence of the diet, /. Nutr. Biochem., 1, 508, 1990. 

Opiate-receptor mediated changes in monoamine synthesis in rat brain Garcia-Sevilla, J. A. Ahtee, Liisa Magnusson, T. Carlsson, A. 

Behavioral inhibition, as assessed on measures like the A-not-B task (Fagen and Ohr, 2001 McCall, 1994). Tasks of this type may be sensitive to nutrients involved in monoamine synthesis (Lozoff et ah, 1998). 

Dopamine. Dopamine (DA) (2) is an intermediate in the synthesis of NE and Epi from tyrosine. DA is localized to the basal ganglia of the brain and is involved in the regulation of motor activity and pituitary hormone release. The actions of DA are terminated by conversion to dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase-A and -B (MAO-A and -B) in the neuron following reuptake, or conversion to homovanillic acid (HVA) through the sequential actions of catechol-0-methyl transferase (COMT) and MAO-A and -B in the synaptic cleft. 

Mitochondrial monoamine oxidase, 1, 253 Mitomycin synthesis, 7, 658, 659 Mitomycin-A, 7, 93 Mitomycin-B, 7, 93 Mitomycin-C, 7, 93 as antitumor drug, 4, 374 Mixed function oxidases, 1, 224 Mobam... 

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 rate of synthesis is similar for trace amines and monoamine neurotransmitters, however, trace amines undergo a more rapid turnover due to their higher affinity to MAO and the lack of comparable cellular storage. Thus, the tissue concentration of trace amines in the vertebrate central nervous system is estimated to be in the range of 1-100 nM, depending on the trace amine and brain area, in contrast to micromolar concentrations of classic monoamine neurotransmitters. 

If a substance is to be a NT it should be possible to demonstrate appropriate enzymes for its synthesis from a precursor at its site of action, although peptides are transported to their sites of location and action after synthesis in the axon or distal neuronal cell body. The specificity of any enzyme system must also be established, especially if they are to be modified to manipulate the levels of a particular NT, or used as markers for it. Thus choline acetyltransferase (ChAT) may be taken as indicative of ACh and glutamic acid decarboxylase (GAD) of GABA but some of the synthesising enzymes for the monoamines lack such specificity. 

One limitation of this method is that the specific activity of the radiolabel is progressively diluted as the radiolabelled transmitter is released from neurons and replaced by that derived from unlabelled substrate. This method also assumes that there is no compartmentalisation of the terminal stores, yet there is ample evidence that newly synthesised acetylcholine and monoamines are preferentially released. An alternative approach is to monitor the rate at which the store of neurotransmitter is depleted after inhibition of its synthesis (Fig. 4.1). However, the rate of release of some neurotransmitters (e.g. 5-HT) is partly governed by their rate of synthesis and blocking synthesis blunts release. 

Figure 4.2 The intraneuronal stores of monoamines are maintained by synthesis from precursors taken in with the diet. The pool is depleted by release of transmitter and some spontaneous metabolism of intraneuronal transmitter. Released monoamines are inactivated by reuptake on membrane-bound transporters. Following reuptake, some transmitter might be recycled while the remainder is metabolised. Some transmitter escapes the reuptake process and overflows from the synapse in the extracellular fluid...

Just as the synthesis of DA and NA is similar so is their metabolism. They are both substrates for monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). In the brain MAO is found in, or attached to, the membrane of the intraneuronal mitochondria. Thus it is only able to deaminate DA which has been taken up into nerve endings and blockade of DA uptake leads to a marked reduction in the level of its deaminated metabolites and in particular DOPAC. The final metabolite, homovanillic... 

Neff, NH and Costa, E (1966) The influence of monoamine oxidase inhibition on catecholamine synthesis. Life Sci. 5 951-959. 

Figure 9.4 The synthesis and metabolism of 5-HT. The primary substrate for the pathway is the essential amino acid, tryptophan and its hydroxylation to 5-hydrox5dryptophan is the rate-limiting step in the synthesis of 5-HT. The cytoplasmic enzyme, monoamine oxidase (MAOa), is ultimately responsible for the catabolism of 5-HT to 5-hydroxyindoleacetic acid...

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...

Grahame-Smith, DG (1971) Studies in vivo on the relationship between brain tryptophan, brain 5HT synthesis and hyperactivity in rats treated with a monoamine oxidase inhibitor and L-tryptophan. J. Neurochem. 18 1053-1066. 

However, experience proves that depression can be reversed by drugs that augment serotonergic and noradrenergic transmission (and reinstated by a deficit in the synthesis of these monoamines). These, then seem to be crucial targets that ultimately determine mood. This would explain why, despite numerous neurochemical options for the causes of depression, all antidepressants developed so far (and even those discovered by chance) target these neuronal systems. Whatever the cause of depression, therefore, its relief seems to rest on appropriate secretion of these monoamines. This would be entirely... 

Typically, neurotoxic effects of drugs on monoamine neurons have been assessed from reductions in brain levels of monoamines and their metabolites, decreases in the maximal activity of synthetic enzymes activity, and decreases in the active uptake carrier. In the present study, the traditional markers described above have been used, including the measurement of the content of monoamines and their metabolites in brain at several different timepoints following drug administration. Since reports in the literature have documented that MDMA and MDA can inhibit the activity of tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis (Stone et al. 1986 Stone et al. 1987). it is unclear whether MDMA-induced reductions in the content of serotonin and its metabolite 5-hydroxyin-doleacetic acid (5-HlAA) may be due to suppressed neurotransmission in otherwise structurally intact serotonin neurons or may represent the eonsequenee of the destruction of serotonin neurons and terminals. 

Mullen DG, Barany G. A new fluoridolyzable linkage for orthogonal solid-phase peptide synthesis Design, preparation, and application of the N-(3 or 4)((4-hydroxymcthyl)-phcnoxy-/butylphenylsilyl)phcnyl pentanedioic acid monoamine (Pbs) handle. J Org Chem 1988 53 5240-5248. 

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