Dopamine cross-sensitization between psychostimulant drugs and stress in healthy male volunteers.

Dysregulation of the stress response system is a potential etiological factor in the development of and relapse to multiple neuropsychiatric disorders. Previously we reported that repeated intermittent d-amphetamine administration can lead to progressively greater dopamine release, thereby providing evidence of drug-induced neurochemical sensitization. Here, we test the hypothesis that repeated exposure to d-amphetamine increases dopaminergic responses to stress; that is, produces cross-sensitization. Using positron emission tomography, we measured in 17 healthy male volunteers (mean ± s.d. = 22.1 ± 3.4 years) [(11)C]raclopride binding responses to a validated psychosocial stress task before and 2 weeks after a regimen of repeated d-amphetamine (3 × 0.3 mg kg(-1), by mouth; n = 8) or placebo (3 × lactose, by mouth; n = 9). Mood and physiological measurements were recorded throughout each session. Before the d-amphetamine regimen, exposure to the stress task increased behavioral and physiological indices of stress (anxiety, heart rate, cortisol, all P ⩽ 0.05). Following the d-amphetamine regimen, the stress-induced cortisol responses were augmented (P < 0.04), and voxel-based analyses showed larger stress-induced decreases in [(11)C]raclopride non-displaceable binding potential across the striatum. In the placebo group, re-exposure to stress led to smaller clusters of decreased [(11)C]raclopride binding, primarily in the sensorimotor striatum (P < 0.05). Together, this study provides evidence for drug × stress cross-sensitization; moreover, random exposure to stimulants and/or stress cumulatively, while enhancing dopamine release in striatal areas, may contribute to a lowered set point for psychopathologies in which altered dopamine neurotransmission is invoked.

α-[11C] methyl-L tryptophan-PET as a surrogate for interictal cerebral serotonin synthesis in migraine without aura.

BACKGROUND: Alteration in central serotonin biology has been implicated in migraine, and serotonin (5-HT) agonists have been available for more than a decade in the treatment of that condition. OBJECTIVES: To test this hypothesis, we studied in vivo using positron-emission tomography (PET) and α-[(11)C] methyl-L-tryptophan (α-[(11)C]MTrp) as a surrogate marker of cerebral 5-HT synthetic rate before and after administration of eletriptan in migraine and control subjects. METHODS: Six nonmenopausal female migraine subjects with migraine without aura (MoA) and six nonmenopausal age-matched female control subjects were scanned at baseline and after oral administration of 40 mg of eletriptan. Migraine subjects at the time of PET had to have been headache free for a minimum of three days. Images of (α-[(11)C]MTrp) brain trapping were colocalized with individual MRI images in three dimensions and analyzed. RESULTS: There was no difference in baseline cerebral global 5-HT synthesis between migraine and control subjects. After administration of eletriptan, there was a striking global reduction in cerebral 5-HT synthesis (K*) in the migraine group and in 22 regions of interest (ROIs). In control subjects, no significant changes were found in global cerebral 5-HT synthesis (K*) or in any of the ROIs. CONCLUSIONS: These findings suggest in migraine an interictal alteration in the regulation mechanisms of cerebral 5-HT synthesis.

Tryptophan hydroxylase(2) gene polymorphisms predict brain serotonin synthesis in the orbitofrontal cortex in humans.

Brain regional serotonin synthesis can be estimated in vivo using positron emission tomography (PET) and α-[((11))C]methyl-L-tryptophan ((11)C-AMT) trapping (K*) as a proxy. Recently, we reported evidence of lower normalized (11)C-AMT trapping in the orbitofrontal cortex (OBFC) of subjects meeting the criteria for an impulsive and/or aggressive behavioral phenotype. In this study, we examined whether part of the variance in OBFC serotonin synthesis is related to polymorphisms of the gene that encodes for the indoleamine's rate-limiting enzyme in the brain, tryptophan hydroxylase-2 (TPH(2)). In all, 46 healthy controls had PET (11)C-AMT scans and were genotyped for 11 single-nucleotide polymorphisms (SNPs) distributed across the TPH(2) gene and its 5' upstream region. Several TPH(2) SNPs were associated with lower normalized blood-to-brain clearance of (11)C-AMT in the OBFC. Dose-effect relationships were found for two variants (rs6582071 and rs4641527, respectively, located in the 5' upstream region and intron 1) that have previously been associated with suicide. Associations in the OBFC remained statistically significant in a mixed larger sample of patients and controls. These results suggest that in humans, genetic factors might partly account for variations in serotonin synthesis in the OBFC.

Time-efficient and convenient synthesis of [(18)F]altanserin for human PET imaging by a new work-up procedure.

[(18)F]Altanserin, an important PET radioligand for the in vivo imaging of the 5-HT(2A) receptor, was synthesized from its precursor nitro-altanserin in DMF or DMSO at high temperatures of 150 degrees C in an overall radiochemical yield (EOB) of 23-25% after 75min. A new solid phase work-up procedure involving the acidification of the crude reaction mixture and a C18-SepPak-solid phase separation preceded the final HPLC purification. This led to a significantly reduced synthesis time as a result of a stable and early elution from the HPLC column using improved HPLC conditions (MeOH/THF/NaOAc 0.05N pH 5: 27/18/55, flow: 5 mL/min, Symetry Prep 7 microm C18 (Waters)). The synthesis was performed semi-automatically in a modified GE TracerLab synthesis module using an in-house-developed program. The synthesized [(18)F]altanserin was used in our ongoing human and animal PET imaging studies.

Sumatriptan normalizes the migraine attack-related increase in brain serotonin synthesis.

BACKGROUND: Altered serotonin (5-HT) neurotransmission has been implicated in the pathophysiology of migraine headache. OBJECTIVES: To test this hypothesis in migraine patients in vivo using PET and alpha-[(11)C]methyl-l-tryptophan as a surrogate marker of brain 5-HT synthetic rate during different phases of their migraine attack and after acute antimigraine therapy with sumatriptan, and to compare them with normal controls. METHODS: Six patients were scanned 1) within 6 hours after the onset of a spontaneous migraine attack, 2) 2 hours after subcutaneous sumatriptan, and 3) interictally when migraine free for at least 3 days. Head pain was rated before each scan, and before and every 15 minutes after sumatriptan. RESULTS: Brain 5-HT synthesis was highest during attacks, lowest after sumatriptan, and intermediate when patients were migraine free. All states were statistically different from the others in virtually all brain regions examined. 5-HT synthetic rates in patients during migraine attacks did not differ from those of age- and sex-matched controls, whereas they were significantly lower after sumatriptan in a majority of regions. Interictally, global brain 5-HT synthetic rate was slightly, albeit not significantly, lower (-14%) in migraine patients than in controls, with specific cortical areas exhibiting proportionally more severe reductions (-28% to 31%). CONCLUSIONS: These findings point to a low cortical serotonergic tone in migraine patients interictally. Further, they demonstrate widespread increases in brain serotonin (5-HT) synthetic rate in migraine patients during attacks, and that triptans exert a negative feedback regulation of brain 5-HT synthesis concurrently with modulation of pain pathways.

Acute prefrontal cortex TMS in healthy volunteers: effects on brain 11C-alphaMtrp trapping.

High-frequency repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (LDLPFC) is a technique with purported efficacy as a treatment for major depression. Here, we assessed in vivo, in healthy volunteers, the effect of acute rTMS of the LDLPFC, relative to the stimulation of the left occipital cortex (LOC), on brain regional serotonin synthesis capacity, using the [(11)C]-alpha-methyl-tryptophan ((11)C-alphaMtrp)/PET method. Ten subjects were studied twice, once following rTMS of the LDLPFC and once following rTMS of the LOC in a randomized counterbalanced order. Three blocks of 15 trains of 10 Hz rTMS were delivered 10 min apart. Behavioural and autonomic measures were recorded before and after each rTMS session. Comparisons of TMS-related changes in regional normalized brain uptake and trapping of (11)C-alphaMtrp (K*) values were carried out using SPM99. Statistically significant regional differences were identified on the basis of an extent threshold of 50 voxels, with a peak threshold of p=0.005 uncorrected. Behavioural and autonomic measures were unaffected by rTMS. Relative to LOC stimulation, LDLPFC rTMS was associated with marked changes in normalized K* in limbic areas, with significantly lower values in the left parahippocampal gyrus (BA 28) and the right insula (BA 13), and higher values in the right cingulate gyrus (BA 31) and cuneus (BA 18). These findings indicate that acute rTMS of the LDLPFC in healthy volunteers modulates aspects of tryptophan/5-HT metabolism in limbic areas. Such adaptive changes may contribute to the mechanism of action of prefrontal rTMS in major depression.

Cortical trapping of alpha-[(11)C]methyl-l-tryptophan, an index of serotonin synthesis, is lower in females than males.

One neural system that may exhibit gender differences is serotonin (5-HT), a neurotransmitter implicated in the regulation of mood, cognitive processes, and impulse-control. However, most of the available evidence of gender-related differences in this system has been indirect and at times contradictory. The objective of the present study was to follow up on preliminary evidence that there are gender differences in brain regional 5-HT synthesis, as measured by trapping of alpha-[(11)C]methyl-l-tryptophan (alpha-[(11)C]MTrp). Sixty-minute dynamic scans were performed in healthy volunteers, 28 women and 31 men. Functional images of the brain trapping constant, used as a proxy for 5-HT synthesis, which correlate in the rat brain with tryptophan's conversion into 5-HT, were transferred to the standardized 3D space. The voxel based comparison was performed by Statistical Parametric Mapping with proportional normalization. There was lower normalized alpha-[(11)C]MTrp trapping in females than males throughout much of the cerebral cortex, including the left middle frontal gyrus, the bilateral inferior frontal gyrus, the bilateral precentral gyrus, the left supramarginal gyrus, the bilateral inferior parietal lobule, the left superior temporal gyrus, the bilateral posterior cingulate gyrus, and the bilateral precuneus. There were no regions in which the normalized trapping was significantly higher in females than in males. Gender differences in sub-cortical sites were not found. Women, compared to men, may have lower rates of this tracer trapping, used as a proxy for 5-HT synthesis, throughout much of the cerebral cortex which is likely related to differences in 5-HT synthesis because relative differences in the normalized trapping should be the same as those in 5-HT synthesis. These differences may be related, at least in part, to previously suggested gender differences in affect, cognitive processes, and susceptibility to 5-HT-related neuropsychiatric and neurological disorders.

Increasing blood oxygen increases an index of 5-HT synthesis in human brain as measured using alpha-[(11)C]methyl-L-tryptophan and positron emission tomography.

The main objective of this investigation was to test the hypothesis that brain serotonin (5-HT) synthesis, as measured by trapping of alpha-[(11)C]methyl-L-tryptophan (alpha-MTrp) using positron emission tomography (PET), can be modulated by changes in blood oxygen. The study involved six healthy participants (three male and three female), who breathed a 15% or 60% oxygen mixture starting 15 min before the injection of tracer and continuing during the entire acquisition period. Participants were injected with up to 12m Ci of alpha-MTrp. Two sets of PET images were acquired while the participants were breathing each of the oxygen mixtures and, after reconstruction, all images were converted into brain functional images illustrating the brain trapping constant K(*) (microL/g/min). The K(*) values were obtained for 12 regions of interest outlined on the magnetic resonance images. The K(*) values obtained at high and low blood oxygen content were compared by paired statistics using Tukey's post hoc correction. As there were no difference in plasma tryptophan concentrations, these K(*) values are directly related to regional 5-HT synthesis. The results showed highly significant increases (50% on average) in brain serotonin synthesis (K(*) values) at high (mean value of 223+/-41 mmHg) relative to low (mean value 77.1+/-7.7 mmHg) blood oxygen levels. This suggests that tryptophan hydroxylase is not saturated with oxygen in the living human brain and that increases in blood oxygen can elevate brain serotonin synthesis.

The effects of the 5-HT3 antagonist, alosetron, on brain serotonin synthesis in patients with irritable bowel syndrome.

Serotonin (5-HT) plays an important role in the pathophysiology of irritable bowel syndrome (IBS). Using alpha-[(11)C]methyl-L-tryptophan-positron emission tomography (PET), it was demonstrated that brain 5-HT synthesis is increased in patients with IBS, in a gender-specific manner. The aims of the study were to evaluate the effects of alosetron on brain 5-HT synthesis in patients with IBS. Six male and five female non-constipation-predominant IBS patients were enrolled. The subjects received alosetron or a placebo for 14 days, separated by a 2-week washout period. On day 14, rectal distensions commenced just prior to the PET scan (which was performed for 80 min), and continued for 20-min periods. The functional images were analysed with SPM99. Alosetron vs placebo treatments, in a randomized, double-blinded, crossover manner, were studied. 5-HT synthesis was greater in several regions in the males than in the females during the alosetron treatment, whereas there was no region in which the females had greater synthesis. There were significant gender-treatment interactions of synthesis in the cingulate gyrus, caudate nucleus, globus pallidus, and cerebellum. The gender differences in the effect of alosetron on brain 5-HT synthesis may be related to the gender differences in the efficacy of alosetron.

Effects of pentadecapeptide BPC157 on regional serotonin synthesis in the rat brain: alpha-methyl-L-tryptophan autoradiographic measurements.

A novel pentadecapeptide, BPC157, was recently reported to have a large spectrum of in vivo activities, from anti-ulcer to central action on the brain dopaminergic system. The mechanisms of these actions are not well understood. In this study, the evaluation of the effects of acute and repeated administration of BPC157 on serotonin (5-HT) synthesis in the rat brain is reported. The alpha-[14C]methyl-L-tryptophan (alpha-MTrp) autoradiographic method was used to measure regional 5-HT synthesis rates. In the first series of experiments, a single dose treatment of BPC157 (10 microg/kg) administered intraperitoneally 40 min before the alpha-MTrp tracer injection significantly reduced the regional rate of 5-HT synthesis in the dorsal thalamus, hippocampus, lateral geniculate body and hypothalamus. 5-HT synthesis rates in the substantia nigra reticulate and medial anterior olfactory nucleus in BPC157 treated rats were significantly higher than in the control rats. No significant change in the synthesis rate was observed in the raphe nuclei. In the second series of experiments, following a 7-day treatment with BPC157 (10 microg/kg; s.c.), a significant reduction in the 5-HT synthesis rate was observed in the dorsal raphe nucleus, and significant increases were observed in the substantia nigra, lateral caudate, accumbens nucleus and superior olive. This data suggests that BPC157, a gut peptide, influences brain 5-HT synthesis in rats, but we cannot determine, from this data, the mechanism of this action.

Effects of acute or chronic administration of anti-migraine drugs sumatriptan and zolmitriptan on serotonin synthesis in the rat brain.

Triptans are 5-HT1 receptor agonists used as anti-migraine drugs. They act primarily on meningeal blood vessels and on trigeminovascular afferents, but they may also exert central effects. We studied the regional effects of acute and chronic treatment with sumatriptan or zolmitriptan on the rate of serotonin (5-HT) synthesis in the rat brain, using the alpha-14C-methyl-L-tryptophan quantitative autoradiographic method. Sumatriptan at low (300 microg/kg, s.c.) and high (1 mg/kg) doses, as well as zolmitriptan (100 microg/kg), acutely decreased (15-40%, P < 0.05-0.001) 5-HT synthetic rate in many brain regions, including the dorsal raphe nucleus. Chronically, sumatriptan (21 days, approximately 300 microg/kg per day via osmotic minipumps) induced significant increases in the 5-HT synthesis rate in many projection areas but had no effect in the dorsal raphe nucleus. The acute effects on 5-HT synthesis rate would be compatible with activation of 5-HT1 autoreceptors that inhibit serotonin release. In contrast, the increased 5-HT synthesis rate observed after chronic sumatriptan might possibly result from a down-regulation/desensitization of 5-HT1 receptors and/or unmasking of excitatory triptan-sensitive 5-HT receptors. Overall, the present findings indicate that not only zolmitriptan but also sumatriptan affect brain serotonergic neurotransmission.

Selective decrease in serotonin synthesis rate in rat brainstem raphe nuclei following chronic administration of low doses of amitriptyline: an effect compatible with an anti-migraine effect.

The effects of chronic, low-dose amitriptyline on serotonin (5-HT) synthesis rate were measured in rat brain using autoradiography and the trapping of alpha-[14C]-methyl-L-tryptophan (alpha-[14C]-MTrp). Rats received amitriptyline (2 mg/kg per day) or saline via intraperitoneal osmotic minipumps for 21 days. Amitriptyline had no effect on any physiological parameters measured, or on free or total plasma tryptophan levels. However, amitriptyline exerted selective decreases of 15% and 17% (P < 0.001) in serotonin synthesis rates in the dorsal and median raphe nuclei, respectively. There was no reduction in any of the projection areas studied, including the cerebral cortex, hippocampus, thalamus, hypothalamus or striatum. The data suggest that chronic low doses of amitriptyline can lead to sustained 5-HT re-uptake inhibition selectively in the raphe nuclei, an effect compatible with tonic activation of 5-HT(1A) autoreceptors and inhibition of 5-HT synthesis. The failure of chronic amitriptyline treatment to affect 5-HT synthesis rate in the projection areas may ensure an adequate regulation of pain pathways implicated in migraine headache, an effect possibly related to amitriptyline anti-migraine efficacy.

Alpha-[11C] methyl-L-tryptophan and glucose metabolism in patients with temporal lobe epilepsy.

OBJECTIVE: To determine whether metabolism in the brain serotonergic system, including the kynurenine pathway, is involved in temporal lobe epilepsy (TLE). METHODS: The authors studied 14 patients with intractable TLE by PET using alpha-[11C] methyl-L-tryptophan (alpha-MTrp) and 2-[18F]-fluoro-deoxy-glucose (FDG) and compared results with 21 healthy control subjects who had alpha-MTrp PET studies. Seven patients had unilateral hippocampal atrophy (HA), and seven had normal hippocampal volumes (NV). The regional uptake constant (K*) for alpha-MTrp and regional FDG uptake were calculated in regions with high serotonergic innervation, including the hippocampus, amygdala, lateral temporal lobe, frontal lobe, thalamus, lenticular nucleus, and cingulate cortex. RESULTS: A significant increase of alpha-MTrp uptake was observed in the hippocampus ipsilateral to the seizure focus in seven TLE patients with NV compared to seven patients with HA as well as to healthy controls. In patients with TLE, glucose utilization in the lateral temporal lobe ipsilateral to the seizure focus was correlated negatively with K* for alpha-MTrp in the ipsilateral hippocampus and positively with K* in the ipsilateral lenticular nucleus and cingulate cortex. Glucose utilization in the frontal lobe ipsilateral to the seizure shows a reduction in the glucose utilization which relates to the increase in the alpha-MTrp uptake in the ipsilateral lateral temporal lobe. CONCLUSION: This study demonstrates dysfunction of the serotonergic system, which could include metabolism through the kynurenine pathway in TLE patients with normal hippocampal volumes. alpha-MTrp PET studies might be useful for lateralizing the epileptic focus in TLE patients with normal hippocampal volumes.

Reduction in serotonin synthesis following acute and chronic treatments with paroxetine, a selective serotonin reuptake inhibitor, in rat brain: an autoradiographic study with alpha-[14C]methyl-L-tryptophan(2).

Serotonin (5-HT) synthesis rates were calculated on the basis of the assumption that trapping of alpha-[14C]methyl-L-tryptophan (alpha-[14C]MTrp) is directly related to brain 5-HT synthesis. In the first series of experiments, an acute intraperitoneal injection of paroxetine (10 mg/kg) produced a significant reduction in 5-HT synthesis in brain structures containing serotonergic cell bodies (the dorsal, median, and pallidum raphe nuclei), as well as in most projection areas: the ventral tegmental area, median forebrain bundle, hippocampus CA3 region, and nigrostriatal structures (substantia nigra, lateral and medial caudate nuclei). The reductions in the projection areas were greater (between 25 and 53%) than in those areas containing serotonergic cell bodies (between 18 and 23%). In the cerebral cortex, 5-HT synthesis rates were not modified by acute paroxetine treatment. In a second series of experiments, rats were treated with paroxetine (10 mg/kg/day, s.c., delivered by osmotic minipumps) for 14 days. There was a marked decrease (39-69%) in 5-HT synthesis in every structure examined. In conclusion, the present data suggest that the effects of paroxetine on 5-HT synthesis in the cerebral cortex are different from its effects in the cell body area of the brainstem.

Localizing value of alpha-methyl-L-tryptophan PET in intractable epilepsy of neocortical origin.

BACKGROUND: [(11)C] alpha-methyl-L-tryptophan (alpha-MTrp) has been developed as a tracer for the study of the synthesis of serotonin in the brain with PET. However, it has been shown that in pathologic conditions the tracer may reflect the activation of kynurenine metabolism. Increased levels of serotonin and quinolinic acid have been described in resected epileptogenic cortex, raising the possibility that alpha-MTrp can localize seizure foci in patients with intractable partial epilepsy. The authors assessed the uptake of alpha-MTrp in 18 patients (11 men, mean +/- SD age 27.1 +/- 10.1 years, range 13 to 54) with intractable partial epilepsy to correlate the PET findings with the epileptogenic area defined by electroclinical and neuroimaging data. METHOD: Seven patients with cortical dysplasia (CD) and 11 with partial epilepsy in which conventional MRI and fluorine-18-deoxyglucose ((18)FDG)-PET studies failed to detect any abnormality were studied. All underwent scalp EEG monitoring during the PET scan to exclude ictal events and estimate the interictal epileptic activity. RESULTS: In seven patients (39%; CD four and cryptogenic partial epilepsy three), PET showed focal increased uptake of alpha-MTrp corresponding to the epileptogenic area. alpha-MTrp uptake in the epileptic focus correlated with the frequency of interictal spikes (r = 0.7, p < 0.05). CONCLUSIONS: alpha-MTrp-PET may be of value in the localization of the epileptogenic area not only in patients with visible dysplastic lesions, but also in those with cryptogenic partial epilepsy.

Study of the brain serotonergic system with labeled alpha-methyl-L-tryptophan.

alpha-Methyl-L-tryptophan (alpha-MTrp) is an artificial amino acid and an analog of tryptophan (Trp), the precursor of the neurotransmitter serotonin (5-HT). In this article we have summarized available data, which suggest that the measurement of the unidirectional uptake of alpha-MTrp and its conversion to 5-HT synthesis rates is a valid approach for the determination of brain 5-HT synthesis rates. The main feature on which the model is based is the trapping of labeled alpha-MTrp in brain tissue. An overview of opposing opinions, which suggest that there is a need for a metabolic conversion of tracer, is also presented and discussed critically. As with all biological modeling there is likely to be room for improvements of the proposed biological model. In addition, there are a limited number of clearly defined circumstances in which the method is confounded by the metabolism of labeled alpha-MTrp via the kynurenine pathway. Nonetheless, a significant body of evidence suggests that labeled alpha-MTrp is a useful tracer to study brain 5-HT synthesis in most circumstances. Calculation of 5-HT synthesis rates depends on the plasma-free tryptophan concentration, which, according to the balance of arguments in the literature, is a more appropriate parameter than the total-plasma tryptophan. The method, as proposed by us, can be used in conjunction with autoradiographic measurements in laboratory animals, and with positron emission tomography in large animals and humans. We review studies in animals looking at the normal control of 5-HT synthesis and the way in which it is altered by drugs, as well as initial studies investigating healthy humans and patients with neuropsychiatric disorders.

Labelled alpha-methyl-L-tryptophan as a tracer for the study of the brain serotonergic system.

The alpha-methyl-L-trypotophan (alpha-MTrp) method for the study of the brain serotonergic system is based on the fact that labelled alpha-MTrp is taken up by and, in part, retained in the brain, and this retention (trapping) is proportional to brain serotonin (5-HT) synthesis. A 3-compartment model is proposed in which the plasma, the precursor and irreversible pools are mathematically distinct compartments. The irreversible compartment is assumed to be the one in which the tracer is trapped. By definition, the tracer from the irreversible compartment does not exchange directly with the plasma compartment. The rate at which labelled alpha-MTrp is trapped is converted to the rate of 5-HT synthesis by dividing it by a conversion factor, called the lumped constant, and multiplying it by the plasma-free tryptophan concentration. Our results revealed that brain 5-HT synthesis can be influenced by the extraneuronal concentration of 5-HT and that, generally, the influence is not uniform throughout the brain. They also suggest that brain trapping of labelled alpha-MTrp relates to 5-HT synthesis. The proposed procedure for converting the rate at which labelled alpha-MTrp is trapped to brain 5-HT synthesis rates is based on measurements that suggest that plasma-free Trp relates to brain 5-HT synthesis. However, as with all biological models, there is likely room for improvement in our approach.

Effects of selective 5-HT1A receptor antagonists on regional serotonin synthesis in the rat brain: an autoradiographic study with alpha-[14C]methyl-L-tryptophan.

The effects of acute and chronic administration of WAY100635 and WAY100135, serotonin (5-HT)1A antagonists, on 5-HT synthesis rates, calculated from the trapping of alpha-[14C]methyl-L-tryptophan (alpha-MTrp), were evaluated in the rat brain using autoradiography. In the acute treatment studies, WAY100635 (1 mg/kg) induced a significant increase in 5-HT synthesis in the median raphe nucleus and some nerve terminal structures (range between 18 and 53%), while WAY100135 (10 mg/kg) produced a significant decrease of synthesis, in the range between 16 and 33%, in the raphe magnus nucleus and several projection areas. The action of WAY100635 given acutely was likely a result of antagonist actions at the 5-HT1A somato-dendritic autoreceptors. WAY100135 probably acted acutely as a partial agonist. In the chronic treatment studies, WAY100635 (1 mg/kg/day) and WAY100135 (10 mg/kg/day) were administered for 7 days as s.c. injections once a day. Chronic treatment with both compounds significantly reduced the rate of 5-HT synthesis in the nerve terminal structures and produced a significant increase in the raphe nuclei. These treatments did not have any effect on the plasma free or total tryptophan.

Brain Regional alpha-[11C]methyl-L-tryptophan trapping in impulsive subjects with borderline personality disorder.

OBJECTIVE: Neurotransmission of serotonin (or 5-hydroxytryptamine [5-HT]) is thought to be disturbed in patients exhibiting impulsive behaviors. However, until recently it has not been possible to test this hypothesis in the brains of living humans. METHOD: Unidirectional trapping of the 5-HT precursor analog alpha-[(11)C]methyl-L-tryptophan (alpha-[(11)C]MTrp) has been proposed as an index of 5-HT synthesis capacity. The authors measured brain regional alpha-[(11)C]MTrp trapping with positron emission tomography in medication-free subjects with borderline personality disorder (N=13) and a healthy comparison group (N=11). Impulsivity was assessed by using a laboratory measure of behavioral disinhibition, go/no-go commission errors. RESULTS: Compared to healthy men, the men with borderline personality disorder had significantly lower alpha-[(11)C]MTrp trapping in corticostriatal sites, including the medial frontal gyrus, anterior cingulate gyrus, superior temporal gyrus, and corpus striatum. In the women with borderline personality disorder, significantly lower alpha-[(11)C]MTrp trapping was seen in fewer regions, but in both men and women, negative correlations with impulsivity scores were identified in the medial frontal gyrus, anterior cingulate gyrus, temporal gyrus, and striatum. CONCLUSIONS: Low 5-HT synthesis capacity in corticostriatal pathways may contribute to the development of impulsive behaviors in persons with borderline personality disorder.