Serotonin precursor tryptophan

Studies in which the availability of serotonin is manipulated in combination with a laboratory panic challenge has considerably increased insight into the relationship between serotonin and panic disorder. Tryptophan depletion caused an increased panic response to a 5% or 35% CO2 challenge in panic disorder patients (Miller et al. 2000 Schruers et al. 2000). Conversely, panic anxiety and symptoms, as well as the number of panic attacks following 35% CO2 inhalation, were significantly reduced by pretreatment with the serotonin precursor L-hydroxytryptophan, suggesting that under certain circumstances serotonin may act to inhibit panic (Schruers et al. 2002). 

A recent positron emission tomography (PET) study in which the radiolabeled serotonin precursor alpha C methyl tryptophan was used provides empirical evidence of decreased 5-HT synthesis in frontal and thalamic regions and increased 5-HT synthesis in contralateral cerebellar dentate regions (Chugani et al., 1997). These findings are consistent with findings of increased 5-HTm inhibitory autoreceptor sensitivity in adult autistic patients (Hollander et al., 2000 Novotny et al., 2000), since these receptors are prevalent in frontal and thalamic, but not cerebellar, regions. 

Some evidence indicates that other drugs with action on the serotonergic system may be associated with efficacy in OCD. Tryptophan, a precursor of serotonin, was shown in a small placebo-controlled study to have an effect size similar to that of the SSRls (S. A. Montgomery et al. 1992). Mianserin, which has 5-HTjq and 5-HT2C receptor affinities, has also been reported in a small placebo-controlled study to be more effective than placebo. This last result raises the possibility that 5-HTjp or 5-HT2C may be the more specific receptors for OCD. The provocation of obsessional symptoms by m-chloro-phenylpiperazine (mCPP), which also has affinities for 5-HT,p and 5-HT2C, reinforces this concept (Zohar et al. 1988a). 

Serotonin precursors (L-tryptophan. 5-hydroxytryptophan) have some antidepressant action, whereas a reduction in the blood levels of tryptophan in remitted depressed patients can provoke clinical relapse. 

FIGURE 18-22 Tryptophan as precursor. The aromatic rings of tryptophan give rise to nicotinate, indoleacetate, and serotonin. Colored atoms trace the source of the ring atoms in nicotinate. 

TCDD was investigated. No changes were found in epinephrine and dopamine in the hypothalamus or in dopamine and its metabolites in the striatum. However, tryptophan (a precursor of serotonin) levels in plasma and brain were increased and this was paralleled by increases in brain serotonin and 5-hydroxyindolacetic acid (the major serotonin metabolite) (Rozman et al. 1991). Based on the results of these experiments, Rozman et al. (1991) proposed that decreased PEPCK activity decreases gluconeogenesis and leads to increased plasma concentrations of glycogenic amino acids, such as tryptophan. Increased tryptophan leads to increase in serotonin release in the brain and to appetite... 

In children who drink juices containing aspartame, hypersensitivity has been observed and an increased tendency toward aggressive behavior has been observed. It has been found that aspartame intake leads to doubling phenylalanine concentration in the central nervous system. Also an increase in tyrosine has been observed, followed by a decrease of tryptophan—a serotonine precursor. Low CNS serotonine in children has been found to be responsible for neurosis symptoms. 

Another test for the biogenic amine hypothesis w ould involve precursor loading sLategies. In other w ords, compounds w hich could increase brain levels of norepinephrine and/or serotonin should demonsLate antidepressant efficacy. Results of these studies have been mixed. Several positive findings w ere reported wdth Seating depression wdth the serotonin precursors tryptophan and 5-hydroxy tryptophan (5-HT) (Shaw et al., 2001), but these w ere not consistently replicated. Less posidve results w ere reported wdth attempts to increase brain norepinephrine levels wdth precursors. 

Lithium s serotonergic activity is postulated to be responsible for its role in preventing depressive episodes of bipolar disorder. Some bipolar patients demonstrate low CNS concentrations of serotonin. Lithium may contribute to serotonin production by increasing the uptake of the tryptophan, a serotonin precursor (American Society of Hospital Pharmacists 1993). 

Neurotransmitters and NREM Sleep in Humans. Several agents that influence the brain levels of neurotransmitters have a profound effect on NREM sleep in humans. Most studies indicate that tryptophan, a precursor of serotonin, increases NREM sleep time and decreases sleep latency (38, 39). Tryptophan was used one time as a sleep-inducing agent, but it is no longer available because it causes eosinophilic myalgia syndrome. 

The amino-acid L-tryptophan, a precursor of serotonin, was once popular as a natural sedative. Cases of eosinophUia-myalgia syndrome, which were most likely due to contamination of excipients, caused this product to be removed from the market. ... 

The involvement of the central nervous system serotonin function in the pathogenesis and treatment of affective disorders has been a subject of intensive research during the past 30 years.33 36 Studies using serotonin precursors and agonists as pharmacologic probes and measurements of cerebrospinal fluid monoamine metabolite levels indicated that alterations in central nervous system serotonin function may be involved in the pathophysiology of depression. Since the synthesis of serotonin depends on dietary intake of the precursor tryptophan, many studies have utilized tryptophan depletion techniques by which patients were fed a tryptophan-free diet for various time intervals. 

Many reports have linked childhood hyperactivity to impaired central serotonin functions.89 In animals, the occurrence of a behavioral syndrome consisting of hyperactivity, stereotyped movements, and increase of temperature has been induced by L-tryptophan, as a serotonin precursor, by serotonin reuptake inhibitors, and by MAOIs.90 Most of these manifestations can be blocked specifically by pretreatment with an inhibitor of serotonin synthesis. In humans, the association of myoclonus, diarrhea, confusion, hypomania, agitation, hyperreflexia, shivering, incoordination, fever, and diaphoresis, when patients are treated with serotoninergic agents, could constitute a "serotonin syndrome." Such cases of serotonin syndrome were reported after treatments with L-tryptophan, MAOIs, serotonin reuptake inhibitors, and tricyclics, alone or in association. 

Individuals who cannot produce 5,6,7,8-tetrahydrobiopterin must be supplied with L-dopa and 5-hydroxy tryptophan, metabolic precursors to norepinephrine and serotonin. Why does supplying 5,6,7,8-tetrahydrobiopterin have no effect ... 

Patients with unipolar depression are effectively treated with drugs, such as chlo-rimipramine and more recently fluoxetine, which are known to block neuronal uptake of serotonin. In addition, giving 5-hydroxy tryptophan (a precursor of serotonin) either alone or in combination with chlorimipramine seems to benefit these patients. 

Serotonin also affects the perception of pain, thermoregulation, and sleep. There are those who believe that a glass of warm milk will help you fall asleep. We have all noticed how sleepy we become after that big Thanksgiving turkey dinner. Both milk protein and turkey are exceptionally high in tryptophan, the precursor of serotonin ... 

Fig. 14.2. Steps involved in serotonergic neurotransmission. The serotonin precursor tryptophan is taken up into the neuron (A) and converted to 5-HT (B). Synthesized 5-HT Is stored in synaptic vesicles (C). Under the appropriate conditions, the synaptic vesicles migrate to and fuse with the cell membrane, releasing their store of 5-HT (D).

Serotonin plays a role in the modulation of social behavior and in reward processing. Deficiency of tryptophan, the serotonin precursor, leads to reduction in serotonin production, and brings about reductions in the level of cooperation shown by participants in an experimental game-playing experiment. Serotonin also plays a role in socially... 

Early studies by Meulemans et al. used differential pulse voltammetry (see Chapter 11) to measure the concentration of electroactive drugs in the cytoplasm of cholinergic neurons of Aplysia californica and to determine rates of cellular uptake and clearance (108). Another report by Meulemans et al. described a needle tipped glass insulated platinum electrode for detection of intracellular serotonin in metacerebral neurons from Aplysia (109). Again differential pulse voltammetry was used to measure intracellular concentration of serotonin after cell stimulation, after injection of serotonin into the cell, and after extracellular treatment with tryptophan, a serotonin precursor. Serotonin concentration in resting untreated cells was determined to be 0.94 0.61 mM. Chen et al. have also used platinum electrodes with multiple pulse voltammetry to measure dopamine levels in the giant dopamine neuron of Planorbis comeus (110). 

Tryptophan Precursor of serotonin precursor of nicotinamide (B-vitamin)... 

L-Tryptophan, a precursor of serotonin has also been shown in normal subjects to reduce sleep latency and Increase sleep length without altering the qualitative characteristics of polygraphically recorded sleep . In a double-blind study in hospitalized insomniac patients, doses of 4 to 5 g of L-tryptophan significantly increased sleep time, reduced sleep latency and reduced the number of awakenings. ... 

Tryptophan is a precursor for a series of metabolic reactions. Two tryptophan catabolizing pathways are well characterized (i) tryptophan converts to serotonin (ii) tryptophan is also converted to kynurenine. 

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