Showing papers on "Serotonin published in 1998"
TL;DR: It is demonstrated that mice without 5-HT1A receptors display decreased exploratory activity and increased fear of aversive environments (open or elevated spaces) and suggested that reductions in 5- HT1A receptor density due to genetic defects or environmental stressors might result in heightened anxiety.
Abstract: To investigate the contribution of individual serotonin (5-hydroxytryptamine; 5-HT) receptors to mood control, we have used homologous recombination to generate mice lacking specific serotonergic receptor subtypes. In the present report, we demonstrate that mice without 5-HT1A receptors display decreased exploratory activity and increased fear of aversive environments (open or elevated spaces). 5-HT1A knockout mice also exhibited a decreased immobility in the forced swim test, an effect commonly associated with antidepressant treatment. Although 5-HT1A receptors are involved in controlling the activity of serotonergic neurons, 5-HT1A knockout mice had normal levels of 5-HT and 5-hydroxyindoleacetic acid, possibly because of an up-regulation of 5-HT1B autoreceptors. Heterozygote 5-HT1A mutants expressed approximately one-half of wild-type receptor density and displayed intermediate phenotypes in most behavioral tests. These results demonstrate that 5-HT1A receptors are involved in the modulation of exploratory and fear-related behaviors and suggest that reductions in 5-HT1A receptor density due to genetic defects or environmental stressors might result in heightened anxiety.
816 citations
TL;DR: In this paper, the authors used gene-targeting technology to generate 5-HT1A receptor-mutant mice and found that these mutants exhibited a consistent pattern of responses indicative of elevated anxiety levels in open field, elevated zero maze, and novel object assays.
Abstract: The brain serotonin (5-hydroxytryptamine; 5-HT) system is a powerful modulator of emotional processes and a target of medications used in the treatment of psychiatric disorders. To evaluate the contribution of serotonin 5-HT1A receptors to the regulation of these processes, we have used gene-targeting technology to generate 5-HT1A receptor-mutant mice. These animals lack functional 5-HT1A receptors as indicated by receptor autoradiography and by resistance to the hypothermic effects of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Homozygous mutants display a consistent pattern of responses indicative of elevated anxiety levels in open-field, elevated-zero maze, and novel-object assays. Moreover, they exhibit antidepressant-like responses in a tail-suspension assay. These results indicate that the targeted disruption of the 5-HT1A receptor gene leads to heritable perturbations in the serotonergic regulation of emotional state. 5-HT1A receptor-null mutant mice have potential as a model for investigating mechanisms through which serotonergic systems modulate affective state and mediate the actions of psychiatric drugs.
723 citations
TL;DR: Data suggest that the presence of a functional 5-HTT is essential for brain 5- HT homeostasis and for 3,4-methylenedioxymethamphetamine-induced hyperactivity.
Abstract: The sodium-dependent, high affinity serotonin [5-hydroxytryptamine (5-HT)] transporter (5-HTT) provides the primary mechanism for inactivation of 5-HT after its release into the synaptic cleft. To further evaluate the function of the 5-HTT, the murine gene was disrupted by homologous recombination. Despite evidence that excess extracellular 5-HT during embryonic development, including that produced by drugs that inhibit the 5-HTT, may lead to severe craniofacial and cardiac malformations, no obvious developmental phenotype was observed in the 5-HTT−/− mice. High affinity [3H]5-HT uptake was completely absent in 5-HTT−/− mice, confirming a physiologically effective knockout of the 5-HTT gene. 5-HTT binding sites labeled with [125I]3β-(4′-iodophenyl)tropan-2β-carboxylic acid methyl ester were reduced in a gene dose-dependent manner, with no demonstrable binding in 5-HTT−/− mutants. In adult 5-HTT−/− mice, marked reductions (60–80%) in 5-HT concentrations were measured in several brain regions. While (+)-amphetamine-induced hyperactivity did not differ across genotypes, the locomotor enhancing effects of (+)-3,4-methylenedioxymethamphetamine, a substituted amphetamine that releases 5-HT via a transporter-dependent mechanism, was completely absent in 5-HTT−/− mutants. Together, these data suggest that the presence of a functional 5-HTT is essential for brain 5-HT homeostasis and for 3,4-methylenedioxymethamphetamine-induced hyperactivity.
708 citations
TL;DR: It is hypothesize that an increased serotonergic neurotransmission is responsible for the anxiety-like behavior of receptor-deficient animals, consistent with earlier studies showing that pharmacological activation of the 5-HT system is anxiogenic in animal models and also in humans.
Abstract: Brain serotonin (5-HT) has been implicated in a number of physiological processes and pathological conditions. These effects are mediated by at least 14 different 5-HT receptors. We have inactivated the gene encoding the 5-HT1A receptor in mice and found that receptor-deficient animals have an increased tendency to avoid a novel and fearful environment and to escape a stressful situation, behaviors consistent with an increased anxiety and stress response. Based on the role of the 5-HT1A receptor in the feedback regulation of the 5-HT system, we hypothesize that an increased serotonergic neurotransmission is responsible for the anxiety-like behavior of receptor-deficient animals. This view is consistent with earlier studies showing that pharmacological activation of the 5-HT system is anxiogenic in animal models and also in humans.
708 citations
TL;DR: Evidence that supports a role for hypothalamic serotonergic receptor mechanisms in the mediation of eating behavior and body weight disorders is reviewed, and a model that proposes the involvement of circulating hormones and glucose in this feedback process is described.
518 citations
TL;DR: The hypothesis to explain why SSRIs have such diverse therapeutic actions is that somatodendritic 5HT1A autoreceptor desensitization increases serotonin in critical brain regions and at those key serotonin receptor subtype(s) which may mediate the pathophysiologies of the various disorders.
482 citations
TL;DR: It is shown that young adult mice with a targeted mutation of the serotonin 5-HT2C receptor gene consume more food despite normal responses to exogenous leptin administration, demonstrating a dissociation of serotonin and leptin signaling in the regulation of feeding and indicating that a perturbation of brain serotonin systems can predispose to type 2 diabetes.
Abstract: Brain serotonin and leptin signaling contribute substantially to the regulation of feeding and energy expenditure. Here we show that young adult mice with a targeted mutation of the serotonin 5-HT
2C
receptor gene consume more food despite normal responses to exogenous leptin administration. Chronic hyperphagia leads to a 'middle-aged'-onset obesity associated with a partial leptin resistance of late onset. In addition, older mice develop insulin resistance and impaired glucose tolerance. Mutant mice also responded more to high-fat feeding, leading to hyperglycemia without hyperlipidemia. These findings demonstrate a dissociation of serotonin and leptin signaling in the regulation of feeding and indicate that a perturbation of brain serotonin systems can predispose to type 2 diabetes.
460 citations
TL;DR: Enhanced radioligand binding of an agonist to inhibitory serotonin-1A autoreceptors in the human DR provides pharmacological evidence to support the hypothesis of diminished activity of serotonin neurons in suicide victims with major depression.
Abstract: It has been hypothesized that a deficit in serotonin may be a crucial determinant in the pathophysiology of major depression. Serotonin-1A receptors are located on serotonin cell bodies in the midbrain dorsal raphe (DR) nucleus, and the activation of these receptors inhibits the firing of serotonin neurons and diminishes the release of this neurotransmitter in the prefrontal cortex. Repeated treatment with some antidepressant medications desensitizes serotonin-1A receptors in the rat midbrain. The present study determined whether the binding of [3H]8-hydroxy-2-(di-n-propyl)aminotetralin (8-OH-DPAT), an agonist at serotonin-1A receptors, is altered in the midbrain of suicide victims with major depression. Radiolabeling of the serotonin-1A receptor in the DR varied significantly along the rostral-to-caudal extent of the human midbrain. The binding of [3H]8-OH-DPAT to serotonin-1A receptors was increased significantly in the midbrain DR of suicide victims with major depression as compared with psychiatrically normal control subjects. In suicide victims with major depression, the increase in the binding of [3H]8-OH-DPAT to serotonin-1A receptors was detected in the entire DR and specifically localized to the dorsal and ventrolateral subnuclei. Enhanced radioligand binding of an agonist to inhibitory serotonin-1A autoreceptors in the human DR provides pharmacological evidence to support the hypothesis of diminished activity of serotonin neurons in suicide victims with major depression.
430 citations
TL;DR: Serotonin transporter binding sites were regulated in a region-specific and substance-specific pattern, which was not simply a local response to functional blockade, and it is possible that serotonin transporter promoter genotype may play a complex role in chronic ethanol dependence.
Abstract: OBJECTIVE: Earlier platelet and postmortem brain studies have found alterations in serotonin transporter function in ethanol-abusing human subjects. The present investigation tested the hypothesis that brain serotonin transporter function is altered in chronic users of ethanol and cocaine, which might be related to a common serotonin transporter promoter polymorphism. METHOD: Serotonin transporter binding sites, serotonin transporter mRNA levels, and serotonin transporter promoter variants were quantified in postmortem samples from a group of human subjects who had been ethanol users or cocaine users and then compared to those of a matched group of comparison subjects. Quantitative autoradiographic and in situ hybridization assays were performed in midbrain samples that contained the dorsal and median raphe nuclei (the location of serotonin cell bodies that innervate the forebrain). RESULTS: There was a significant overall cocaine-by-ethanol-by-genotype interaction. Dorsal raphe [125I]CIT binding to the s...
399 citations
TL;DR: Data indicate that such antidepressant treatments, acting on entirely different primary targets, might alleviate depression by enhancing the tonic activation of forebrain postsynaptic 5-HT1Areceptors.
Abstract: We report here the first direct functional evidence of an increase in the tonic activation of postsynaptic 5-HT1A receptors by antidepressant treatments. Because 5-HT1A receptor activation hyperpolarizes and inhibits CA3 pyramidal neurons in the dorsal hippocampus, we determined, using in vivo extracellular recording, whether the selective 5-HT1A receptor antagonist WAY 100635 could disinhibit these neurons. Unexpectedly, no disinhibition could be detected in controls. However, after long-term treatment with the tricyclic antidepressant imipramine, the selective 5-HT reuptake inhibitor paroxetine, the reversible monoamine oxidase-A inhibitor befloxatone, the alpha2-adrenergic antagonist mirtazapine, or the 5-HT1A receptor agonist gepirone or multiple electroconvulsive shock (ECS) administration, WAY 100635 markedly increased (60-200%) the firing activity of CA3 pyramidal neurons. Such a disinhibition was absent in rats treated with the nonantidepressant drug chlorpromazine, in rats receiving only one ECS, or in rats receiving multiple ECSs in combination with an intrahippocampal pertussis toxin treatment to inactivate Gi/o-coupled 5-HT1A receptors. These data indicate that such antidepressant treatments, acting on entirely different primary targets, might alleviate depression by enhancing the tonic activation of forebrain postsynaptic 5-HT1A receptors.
352 citations
Journal Article•
TL;DR: The results of a series of investigations confirm the importance of monoamines in the mediation of depressed mood, but also suggest that other brain neural systems may have more of a primary role than previously thought in the pathophysiology of depression.
Abstract: Alterations in noradrenergic and serotonergic function in the central nervous system (CNS) have been implicated in the pathophysiology of depression and the mechanism of action of antidepressant drugs Based on changes in norepinephrine and serotonin metabolism in the CNS, it has been postulated that subgroups of patients with differential responses to norepinephrine and serotonin reuptake inhibitors may exist Alpha-methylparatyrosine (AMPT), which causes rapid depletion of brain catecholamines, has been used as a noradrenergic probe to test the hypothesis that changes in neurotransmission through the catecholamine system may underlie the therapeutic response to norepinephrine reuptake inhibitors Brain serotonin is dependent on plasma levels of the essential amino acid tryptophan Rapid tryptophan depletion, in the form of a tryptophan-free amino acid drink, has been used as a serotonergic probe to identify therapeutically responsive subsets of patients Using these probes, we have recently examined the behavioral effects of reduced concentrations of brain monoamines on depressed patients treated with a variety of serotonin selective reuptake inhibitors (SSRIs) or the relatively norepinephrine-selective antidepressant desipramine, during 3 different states: drug-free and depressed; in remission on antidepressant drugs; and drug-free in remission The results of a series of investigations confirm the importance of monoamines in the mediation of depressed mood, but also suggest that other brain neural systems may have more of a primary role than previously thought in the pathophysiology of depression Noradrenergic and serotonergic probes may be used in time to identify subsets of depressed patients to determine which patients might respond differentially to the new selective norepinephrine reuptake inhibitors or SSRIs
TL;DR: It is proposed that even drug-naive 5-HT1B-knockout mice are in a behavioural and biochemical state that resembles that of wild-type mice sensitized to cocaine by repeated exposure to the drug, which might be responsible for their increased vulnerability to cocaine.
Abstract: There is increasing evidence that genetic factors can influence individual differences in vulnerability to drugs of abuse1,2. Serotonin (5-hydroxytryptamine, 5-HT), acting through many receptors can modulate the activity of neural reward pathways and thus the effects of various drugs of abuse3,4,5,6,7,8. Here we examine the effects of cocaine in mice lacking one of the serotonin-receptor subtypes, the 5-HT1B receptor9. We show that mice lacking 5-HT1B display increased locomotor responses to cocaine and that they are more motivated to self-administer cocaine. We propose that even drug-naive 5-HT1B-knockout mice are in a behavioural and biochemical state that resembles that of wild-type mice sensitized to cocaine by repeated exposure to the drug. This altered state might be responsible for their increased vulnerability to cocaine.
TL;DR: It is shown that hOCT2 message and protein are expressed in neurons of the cerebral cortex and in various subcortical nuclei and that amantadine does not interact with the expressed human Na+/Cl- dopamine cotransporter.
Abstract: Recently, we cloned the human cation transporter hOCT2, a member of a new family of polyspecific transporters from kidney, and demonstrated electrogenic uptake of tetraethylammonium, choline, N1-methylnicotinamide, and 1-methyl-4-phenylpyridinium. Using polymerase chain reaction amplification, cDNA sequencing,in situ hybridization, and immunohistochemistry, we now show that hOCT2 message and protein are expressed in neurons of the cerebral cortex and in various subcortical nuclei. In Xenopus laevis oocytes expressing hOCT2, electrogenic transport of norepinephrine, histamine, dopamine, serotonin, and the antiparkinsonian drugs memantine and amantadine was demonstrated by tracer influx, tracer efflux, electrical measurements, or a combination. Apparent Km values of 1.9 ± 0.6 mm (norepinephrine), 1.3 ± 0.3 mm (histamine), 0.39 ± 0.16 mm (dopamine), 80 ± 20 μm(serotonin), 34 ± 5 μm (memantine), and 27 ± 3 μm (amantadine) were estimated. Measurement of trans-effects in depolarized oocytes and human embryonic kidney cells expressing hOCT2 suggests that there were different rates and specificities for cation influx and efflux. The hypothesis is raised that hOCT2 plays a physiological role in the central nervous system by regulating interstitial concentrations of monoamine neurotransmitters that have evaded high affinity uptake mechanisms. We show that amantadine does not interact with the expressed human Na+/Cl− dopamine cotransporter. However, concentrations of amantadine that are effective for the treatment of Parkinson′s disease may increase the interstitial concentrations of dopamine and other aminergic neurotransmitters by competitive inhibition of hOCT2.
TL;DR: The hypothesis of serotonergic dysfunction in alcoholism and in withdrawal-emergent depressive symptoms is supported, which was significantly correlated with lifetime alcohol consumption and with ratings of depression and anxiety during withdrawal.
Abstract: Objective:Dysfunction of monoamine uptake mechanisms has been implicated in the pathogenesis of alcohol dependence. The authors explored whether serotonergic dysfunction is associated with anxiety and depression, which increase the risk of relapse in alcoholics.Method:The availability of serotonin and dopamine transporters in 22 male alcoholics and 13 healthy male volunteers was measured with the use of [123I]β-CIT and single photon emission computed tomography, and psychopathological correlates were assessed.Results:A significant reduction (a mean of about 30%) in the availability of brainstem serotonin transporters was found in the alcoholics, which was significantly correlated with lifetime alcohol consumption and with ratings of depression and anxiety during withdrawal.Conclusions:The findings support the hypothesis of serotonergic dysfunction in alcoholism and in withdrawal-emergent depressive symptoms. Am J Psychiatry 1998; 155: 1544-1549
TL;DR: Data suggest that TRP depletion results in substantial declines in central 5-HT turnover, which is similar to that observed in healthy adult subjects after a one-day low-TRP diet and a TRP-free amino acid drink.
TL;DR: The data suggest that 5-HT2C receptors exert a tonic, inhibitory influence upon frontocortical dopaminergic and adrenergic, but not serotonergic, transmission.
TL;DR: The nocturnal increase in circulating melatonin in vertebrates is regulated by 10- to 100-fold increases in pineal serotonin N-acetyltransferase (AA-NAT) activity, and adrenergic-cAMP regulation of AA-NAT is mediated by rapid reversible control of selective proteasomal proteolysis.
Abstract: The nocturnal increase in circulating melatonin in vertebrates is regulated by 10- to 100-fold increases in pineal serotonin N-acetyltransferase (AA-NAT) activity. Changes in the amount of AA-NAT protein were shown to parallel changes in AA-NAT activity. When neural stimulation was switched off by either light exposure or L-propranolol-induced beta-adrenergic blockade, both AA-NAT activity and protein decreased rapidly. Effects of L-propranolol were blocked in vitro by dibutyryl adenosine 3',5'-monophosphate (cAMP) or inhibitors of proteasomal proteolysis. This result indicates that adrenergic-cAMP regulation of AA-NAT is mediated by rapid reversible control of selective proteasomal proteolysis. Similar proteasome-based mechanisms may function widely as selective molecular switches in vertebrate neural systems.
TL;DR: In women, oestrogen is thought to protect against depression and delay the onset of schizophrenia and Alzheimer's disease.
Abstract: 1. Sex steroid hormones exert profound effects on mood and mental state. Thus, in women, oestrogen is thought to protect against depression and delay the onset of schizophrenia and Alzheimer's disease. 2. Our studies in the female rat show that oestradiol, in its positive feedback mode for gonadotrophin release, increases the expression of genes for the 5-hydroxytryptamine 5-HT2A receptor and the serotonin transporter (SERT) in the dorsal raphe nucleus and the density of 5-HT2A receptor and SERT sites in regions of the forebrain that, in the human, are concerned with cognition, mental state, emotion and memory. 3. In the male rat, castration decreases while oestrogen and testosterone, but not 5 alpha-dihydrotestosterone (5 alpha-DHT), increase the density of 5-HT2A receptors in forebrain. The fact that 5 alpha-DHT has no effect suggests that the action of testosterone depends on its conversion to oestradiol by aromatase. 4. In intact rats, the density of 5-HT2A receptors in cerebral cortex is significantly higher in pro-oestrous female than in male and dioestrous female rats, showing that the spontaneous, preovulatory surge of oestradiol that reaches a peak at 12.00 h of pro-oestrus also increases the density of 5-HT2A receptors in cortex. 5. Oestrogen and testosterone (by way of its conversion to oestrogen) also stimulate the expression of the arginine vasopressin gene in the bed nucleus of the stria terminalis of the rodent, a mechanism that plays a key role in olfactory memory. 6. These actions of sex steroid hormones are discussed in the context of genomic versus non-genomic mechanisms, the recent discovery that there are two oestradiol receptors with different distributions in brain, the significance of our findings for our understanding of the control of mood, mental state and memory and the mechanism by which oestrogen stimulation of the 5-HT2A receptor could delay the onset of Alzheimer's disease.
TL;DR: Results suggest that discrete domains of the receptor structure are important for ligand binding, G-protein coupling, and internalization, as well as a model for regulation of 5-HT2-family receptors by receptor-mediated endocytosis.
TL;DR: It is found that in the C57BL/6J strain, AANat mRNA encodes a severely truncated AANAT protein, because a pseudo-exon containing a stop codon is spliced in, the first identification of a natural mutation which knocks down melatonin synthesis.
TL;DR: Up-regulation of the cAMP and BDNF systems has resulted in a novel model for the mechanism of action of antidepressants and new targets for the development of therapeutic agents.
TL;DR: The role of specific serotonin receptor antagonists such as cyproheptadine in the treatment of the serotonin syndrome remains to be delineated and its use should be considered an adjunct to supportive care.
Abstract: The serotonin syndrome is the result of excess stimulation of central nervous 5-hydroxytryptamine (5HT)-1a and 5HT-2 receptors. The diagnosis requires a history of exposure to agents active at serotonin receptors and the presence of alterations in mental status, autonomic instability, and neuromuscular abnormalities such as tremor, hyperreflexia, or myoclonus. In this descriptive case series, five cases of serotonin syndrome are reported. All patients gave a history of recent exposure to one or more serotonergic medications, including moclobemide, paroxetine, sertraline, and venlafaxine, with clinical evidence of serotonin syndrome. All patients were administered cyproheptadine (4-8 mg orally) for serotonergic signs. Three had complete resolution of signs within 2 h of administration. Another two had a residual tremor or hyperreflexia following the first dose, which resolved following a repeat dose. There were no adverse outcomes from cyproheptadine use. The role of specific serotonin receptor antagonists such as cyproheptadine in the treatment of the serotonin syndrome remains to be delineated. Its use should be considered an adjunct to supportive care. Currently, it is unknown whether cyproheptadine modifies patient outcome.
TL;DR: Results suggest that CRF is positioned to regulate the function of the dorsal raphe serotonergic system via actions within the cell body region, and this regulation may play a role in stress-related psychiatric disorders in which 5-HT has been implicated.
TL;DR: There is an activation of the immune-inflammatory response system in primary sleep disorders and depression and the decreased availability of plasma tryptophan may be related to the inflammatory system response.
TL;DR: Plasma and platelet levels of amino acids tended to be higher in depressed patients than in healthy controls and Tryptophan/large neutral amino acids ratio (trp/LNAAs) was significantly lower in depressed Patients.
Abstract: Plasma and platelet levels of 18 amino acids were measured in 29 outpatients (mean age ± SD 4741 ± 1085 years; 14 F, 15 M) affected by major depression (DSM IV) and in 28 healthy volunteers (mean age 4246 ± 1419 years; 12 F, 16 M) Plasma and platelet levels of amino acids tended to be higher in depressed patients than in healthy controls In particular, glutamate, taurine and lysine plasma levels and aspartate, serine and lysine platelet levels were significantly higher Tryptophan/large neutral amino acids ratio (trp/LNAAs) was significantly lower in depressed patients Fluvoxamine treatment did not influence plasma and platelet levels of amino acids or trp/LNAAs ratio
TL;DR: Autoradiography found that [3H]citalopram bound to all major 5-HT fibers, not only in the terminal regions, but also in 5- HT axonal bundles such as the cingulum bundle and medial forebrain bundle, and voltammetry recordings indicated that serotonin axonal bundle were actively engaged in high affinity serotonin uptake.
TL;DR: The interaction of melatonin and its precursors with aluminium, cadmium, copper, iron, lead, and zinc: An adsorptive voltammetric study.
Abstract: Melatonin, a pineal secretory product, and its precursors, tryptophan and serotonin, were examined for their metal binding affinities for both essential and toxic metals: aluminium, cadmium, copper, iron, lead, and zinc. An electrochemical technique, adsorptive stripping voltammetry, showed the varying abilities of melatonin and its precursors to bind the metals in situ. The results show that the following metal complexes were formed: aluminium with melatonin, tryptophan, and serotonin; cadmium with melatonin and tryptophan; copper with melatonin and serotonin; iron(III) with melatonin and serotonin; lead with melatonin, tryptophan, and serotonin; and zinc with melatonin and tryptophan. Iron(II) showed the formation of an in situ complex with tryptophan only. These studies suggest a further role for melatonin in the reduction of free radical generation and metal detoxification, and they may explain the accumulation of aluminium in Alzheimer's disease.
TL;DR: There is a complex pattern of reciprocal autoreceptor and heteroceptor control of monoamine release in the frontal cortex of freely-moving rats using a novel and exceptionally sensitive method of high-performance liquid chromatography coupled to coulometric detection.
TL;DR: The results suggest that one action of E replacement therapy in postmenopausal women may be to decrease expression of the SERT gene.
Journal Article•
TL;DR: Therapeutic administration of 5-HTP has been shown to be effective in treating a wide variety of conditions, including depression, fibromyalgia, binge eating associated with obesity, chronic headaches, and insomnia.
Abstract: Hydroxytryptophan (5- HTP) is the intermediate metabolite of the essential amino acid L-tryptophan (LT) in the biosynthesis of serotonin. Intestinal absorption of 5-HTP does not require the presence of a transport molecule, and is not affected by the presence of other amino acids; therefore it may be taken with meals without reducing its effectiveness. Unlike LT, 5-HTP cannot be shunted into niacin or protein production. Therapeutic use of 5-HTP bypasses the conversion of LT into 5-HTP by the enzyme tryptophan hydroxylase, which is the rate-limiting step in the synthesis of serotonin. 5- HTP is well absorbed from an oral dose, with about 70 percent ending up in the bloodstream. It easily crosses the blood-brain barrier and effectively increases central nervous system (CNS) synthesis of serotonin. In the CNS, serotonin levels have been implicated in the regulation of sleep, depression, anxiety, aggression, appetite, temperature, sexual behavior, and pain sensation. Therapeutic administration of 5-HTP has been shown to be effective in treating a wide variety of conditions, including depression, fibromyalgia, insomnia, binge eating associated with obesity, chronic headaches, and insomnia. (Altern Med Rev 1998;3(4):271-280)