Regional Serotonin Synthesis Research Articles

Brain serotonin synthesis capacity in obsessive-compulsive disorder: effects of cognitive behavioral therapy and sertraline

Cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) are both effective treatments for some patients with obsessive-compulsive disorder (OCD), yet little is known about the neurochemical changes related to these treatment modalities. Here, we used positron emission tomography and the α-[11C]methyl-l-tryptophan tracer to examine the changes in brain regional serotonin synthesis capacity in OCD patients following treatment with CBT or SSRI treatment. Sixteen medication-free OCD patients were randomly assigned to 12 weeks of either CBT or sertraline treatment. Pre-to-post treatment changes in the α-[11C]methyl-l-tryptophan brain trapping constant, K* (ml/g/min), were assessed as a function of symptom response, and correlations with symptom improvement were examined. Responders/partial responders to treatment did not show significant changes in relative regional tracer uptake; rather, in responders/partial responders, 12 weeks of treatment led to serotonin synthesis capacity increases that were brain-wide. Irrespective of treatment modality, baseline serotonin synthesis capacity in the raphe nuclei correlated positively with clinical improvement. These observations suggest that, for some patients, successful remediation of OCD symptoms might be associated with greater serotonergic tone.

Both acute and subchronic treatments with pindolol, a 5-HT1A and β1 and β2 adrenoceptor antagonist, elevate regional serotonin synthesis in the rat brain: An autoradiographic study

Antidepressant treatments, including those that increase serotonin (5-HT) neurotransmission, require several weeks or months until the onset of the therapeutic effect in depressed patients. The negative feedback on 5-HT transmission exhibited by the 5-HT1A and 5-HT1B autoreceptors has been postulated as a possible delaying factor. The aim of the present study was to assess the effect of the acute and subchronic treatment with pindolol, a 5-HT1A/1B, β1 and β2 adrenoceptor antagonist, on 5-HT synthesis, one of the key parameters of 5-HT neurotransmission. Male Sprague–Dawley (SPD) rats (180–220g) were treated with pindolol or an adequate volume of saline, administered either acutely (15mg/kg i.p.; SPD-AC-SAL, SPD-AC-TR) or subchronically (15mg/kgday i.p. for 7days; SPD-SUBCHR-SAL, SPD-SUBCHR-TR). Thirty minutes following the single i.p. injection (acute experiment) or at the 8th day following the commencement of the subchronic treatment (subchronic experiment), 5-HT synthesis was measured using α-[14C]methyl-l-tryptophan autoradiography. The analysis of variance (ANOVA), followed by the Benjamini–Hochberg correction for multiple comparisons, revealed: (1) a significant increase of 5-HT synthesis in the SPD-AC-TR rats, relative to the SPD-AC-SAL rats in all brain regions examined except the substantia nigra – pars reticularis, dorsal subiculum, inferior olive, raphe magnus and raphe obscurus and (2) a significant increase of 5-HT synthesis in the SPD-SUBCHR-TR rats, relative to the SPD-SUBCHR-SAL rats in all brain regions except the median raphe, hypothalamus and raphe pontine. On the basis of these results, we hypothesized that the antagonism of the 5-HT1A/1B receptors prevents the negative feedback mediated by these receptors on 5-HT synthesis, resulting in a persistent increase of 5-HT synthesis. The results accord with clinical reports on the utility of pindolol in the augmentation of antidepressant treatment.

Tryptophan hydroxylase2 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.

Acute desipramine treatment reduces regional serotonin synthesis rates, while chronic treatment elevates rates, in a rat model of depression: An autoradiographic study

It has been suggested that 5-HT (serotonin; 5-hydroxytryptamine) and/or the norepinephrine receptor adaptive processes in the brain are the basis for the efficacy of antidepressant treatments, including electro-convulsive shock therapy. In the present study, the effect of acute (10 mg/kg; i.p. injection) and chronic (10 mg/kg/day; delivered by subcutaneous mini-pump) desipramine treatments on regional 5-HT synthesis were evaluated in the Flinders Sensitive Line (FSL; “depressed” rats), as well as the control Flinders Resistant Line (FRL), of rats, using α-[ 14C]methyl- l-tryptophan autoradiography. The control rats in each of the strains received the same volume (volume in which drug was dissolved) of saline (whether through an injection or, in the case of the chronic experiments, via an osmotic mini-pump), while the treated rats received desipramine (DMI) dissolved in saline (again, as an i.p. injection or by osmotic mini-pump). The rats were randomly assigned to different groups. The results indicate that acute treatment produces a reduction in regional 5-HT synthesis in both the FSL and FRL rats, while chronic treatment produces an elevation of regional 5-HT synthesis in both strains, but the effect was somewhat greater in the FRL rats. When comparing these results to those of normal Sprague–Dawley rats, our results suggest that it is more informative to study 5-HT synthesis in an animal model of depression.

AGN-2979, an inhibitor of tryptophan hydroxylase activation, does not affect serotonin synthesis in Flinders Sensitive Line rats, a rat model of depression, but produces a significant effect in Flinders Resistant Line rats

The neurotransmitter, serotonin, is involved in several brain functions, including both normal, physiological functions, and pathophysiological functions. Alterations in any of the normal parameters of serotonergic neurotransmission can produce several different psychiatric disorders, including major depression. In many instances, brain neurochemical variables are not able to be studied properly in humans, thus making the use of good animal models extremely valuable. One of these animal models is the Flinders Sensitive Line (FSL) of rats, which has face, predictive and constructive validities in relation to human depression. The objective of this study was to quantify the effect of the tryptophan hydroxylase (TPH) activation inhibitor, AGN-2979, on the FSL rats (rats with depression-like behaviour), and compare it to the effect on the Flinders Resistant Line (FRL) of rats used as the control rats. The effect was evaluated by measuring changes in regional serotonin synthesis in the vehicle treated rats (FSL-VEH and FRL-VEH) relative to those measured in the AGN-2979 treated rats (FSL-AGN and FRL-AGN). Regional serotonin synthesis was measured autoradiographically in more than 30 brain regions. The measurements were performed using α-[ 14C]methyl- l-tryptophan as the tracer. The results indicate that AGN-2979 did not produce a significant reduction of TPH activity in the AGN-2979 group relative to the vehicle group (a reduction would have been observed if there had been an activation of TPH by the experimental setup) in the FSL rats. On the other hand, there was a highly significant reduction of synthesis in the FRL rats treated by AGN-2979, relative to the vehicle group. Together, the results demonstrate that in the FSL rats, AGN-2979 does not affect serotonin synthesis. This suggests that there was no activation of TPH in the FSL rats during the experimental procedure, but such activation did occur in the FRL rats. Because of this finding, it could be hypothesized that TPH in the FSL rats cannot be easily activated. This may contribute to the development of depressive-like symptoms in the FSL rats (“depressed” rats), as they cannot easily modulate their need for elevated amounts of this neurotransmitter, and possibly other neurotransmitters. Further, because these rats represent a very good model of human depression, one can hypothesize that humans who do not have readily activated TPH may be more prone to develop depression.

Alterations in Brain Serotonin Synthesis in Male Alcoholics Measured Using Positron Emission Tomography

A consistent association between low endogenous 5HT function and high alcohol preference has been observed, and a number of serotonergic manipulations (uptake blockers, agonists) alter alcohol consumption in animals and humans. Studies have also shown an inverse relationship between alcohol use and cerebrospinal fluid levels of serotonin metabolites, suggesting that chronic alcohol consumption produces alterations in serotonin synthesis or release. The objective of the study was to characterize regional brain serotonin synthesis in nondepressed chronic alcoholics at treatment entry in comparison to normal nonalcoholic controls using PET and the tracer alpha-[(11)C]-methyl-L-tryptophan. Comparisons of the alcoholics and controls by SPM found that there were significant differences in the rate of serotonin synthesis between groups. Serotonin synthesis was significantly lower among alcoholics in Brodmann Area (BA) 9, 10, and 32. However, serotonin synthesis among the alcoholics group was significantly higher than controls at BA19 in the occipital lobe and around the transverse temporal convolution in the left superior temporal gyrus (BA41). In addition, there were correlations between regional serotonin synthesis and a quantity-frequency measure of alcohol consumption. Regions showing a significant negative correlation with QF included the bilateral rectus gyri (BA11) in the orbitofrontal area, the bilateral medial frontal area (BA6), and the right amygdala. Current alcoholism is associated with serotonergic abnormalities in brain regions that are known to be involved in planning, judgment, self-control, and emotional regulation.

TPH2 polymorphism, social, psychological and physical adversity during development and brain regional serotonin synthesis capacity in young adult males, followed prospectively since childhood for aggressive behavior at kindergarten

Event Abstract Back to Event TPH2 polymorphism, social, psychological and physical adversity during development and brain regional serotonin synthesis capacity in young adult males, followed prospectively since childhood for aggressive behavior at kindergarten L. Booij1, R. E. Tremblay2, P. Gravel1, J. Séguin3, F. Vitaro4, M. Leyton1, E. Perreau-Linck1, M. Lévesque1, F. Durand1, M. Diksic5, G. Turecki6 and Chawki Benkelfat1* 1 McGill University, Departments of Psychiatry and Neurology, Canada 2 University of Montreal, Departments of Pediatrics, Psychiatry and Psychology, Canada 3 University of Montreal, Department of Psychiatry, Canada 4 University of Montreal, Departments of Psycho-education, Canada 5 McGill University, Departments of Neurology and Neurosurgery, Canada 6 McGill University, McGill Group for Suicide Studies, Canada Background: Low serotonin (5-HT) neurotransmission is one of the mechanisms central to the neurobiology of aggression. A caveat for most of the studies using a cross-sectional design, focusing on patients, whose history is often reconstructed a-posteriori and lacks a developmental perspective, can hardly resolve trait from state abnormalities. This study tested in a population-based cohort sample the hypothesis that adults with a high physical aggression developmental trajectory in childhood/adolescence have reduced 5-HT synthesis capacity. Second aim was to test whether prospective measures of early adversity predict reduced serotonin synthesis capacity. Brain regional 5-HT synthesis was indexed by Positron Emission Tomography and α - [11C]-Methyl-l-Tryptophan blood-to-brain clearance/trapping (K*). Methods: 8 subjects with and 18 without high physical aggression in childhood were tested. Subjects were members of the Montreal cohort of kindergarten schoolchildren (N=1037), followed regularly since childhood for various biological and psychosocial risk factors. Sixty-minute dynamic PET scans were conducted, following injection of α - [11C]-Methyl-l-Tryptophan. Results: Subjective measures of aggression confirmed that individuals in the high physical developmental aggression trajectory exhibited behaviors that are more aggressive during childhood and adolescence, but not in adulthood. Males with a high physical aggression trajectory demonstrated a specific bilateral decrease in normalized K* in the lateral OBFC, relative to the favorable trajectories. (Pre) birth adversity predicted 5-HT synthesis in parts of the medial OBFC and hippocampus, irrespective of trajectory. Conclusion: Low 5-HT synthesis in the OBFC may represent a contributing trait increasing risk for a physical aggression developmental trajectory. Pre (birth) adversity might pose individuals at risk for developing 5-HT related disorders. Keywords: adversity, Aggression, Neuro-development, Neuro-imaging, Serotonin Conference: 3rd Mediterranean Conference of Neuroscience , Alexandria, Egypt, 13 Dec - 16 Dec, 2009. Presentation Type: Oral Presentation Topic: Symposium 14 – Serotonin neurobiology: new vistas Citation: Booij L, Tremblay RE, Gravel P, Séguin J, Vitaro F, Leyton M, Perreau-Linck E, Lévesque M, Durand F, Diksic M, Turecki G and Benkelfat C (2009). TPH2 polymorphism, social, psychological and physical adversity during development and brain regional serotonin synthesis capacity in young adult males, followed prospectively since childhood for aggressive behavior at kindergarten. Front. Neurosci. Conference Abstract: 3rd Mediterranean Conference of Neuroscience . doi: 10.3389/conf.neuro.01.2009.16.057 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 19 Nov 2009; Published Online: 19 Nov 2009. * Correspondence: Chawki Benkelfat, McGill University, Departments of Psychiatry and Neurology, Montréal, Canada, chawki.benkelfat@mcgill.ca Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers L. Booij R. E Tremblay P. Gravel J. Séguin F. Vitaro M. Leyton E. Perreau-Linck M. Lévesque F. Durand M. Diksic G. Turecki Chawki Benkelfat Google L. Booij R. E Tremblay P. Gravel J. Séguin F. Vitaro M. Leyton E. Perreau-Linck M. Lévesque F. Durand M. Diksic G. Turecki Chawki Benkelfat Google Scholar L. Booij R. E Tremblay P. Gravel J. Séguin F. Vitaro M. Leyton E. Perreau-Linck M. Lévesque F. Durand M. Diksic G. Turecki Chawki Benkelfat PubMed L. Booij R. E Tremblay P. Gravel J. Séguin F. Vitaro M. Leyton E. Perreau-Linck M. Lévesque F. Durand M. Diksic G. Turecki Chawki Benkelfat Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Acute prefrontal cortex TMS in healthy volunteers: Effects on brain 11C-αMtrp 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.

Effects of anpirtoline on regional serotonin synthesis in the rat brain: an autoradiographic study

Anpirtoline has been described as an agonist at 5-HT1B receptors with a relatively high potency. It also acts as an agonist at 5-HT1A receptors, but has a lower potency than at the 5-HT1B sites. There is very little known about the mechanism by which anpirtoline influences regional 5-HT synthesis. The aim of the present study was to investigate the effects of acutely and chronically administered anpirtoline on 5-HT synthesis in the rat brain using the autoradiographic alpha-[14C]methyl-L-tryptophan method. In the acute study, anpirtoline (2.0 mg/kg) was administered intraperitoneally 30 min before the tracer injection. The control rats were injected with the same volume of saline. In the chronic study, anpirtoline (2 mg/kg per day) was injected subcutaneously in saline once a day for 10 days. There were no significant differences between the plasma-free and total tryptophan concentrations between the anpirtoline treatment and the respective control groups. In the acute experiment, 5-HT synthesis rates in all of the brain areas investigated were significantly decreased by anpirtoline when compared to the saline-treated group. In the chronic anpirtoline experiment, 5-HT synthesis rates of almost all of the projection areas, as well as the raphe nuclei, were normalized or had a tendency to be normalized. These results suggest that it is likely that the terminal 5-HT1B receptors are involved in the regulation of 5-HT synthesis in the projection areas and that 5-HT synthesis, in the raphe, is likely influenced by anpirtoline's 5-HT1A and/or 5-HT1B agonistic properties.

S.04.04 Abnormalities in behaviour and reduction in expression of specific hippocampal genes genes by prenatal stress in female offspring are reversed by neonatal handling

The neurotransmitter, serotonin, is involved in several brain functions, including both normal, physiological functions, and pathophysiological functions. Alterations in any of the normal parameters of serotonergic neurotransmission can produce several different psychiatric disorders, including major depression. In many instances, brain neurochemical variables are not able to be studied properly in humans, thus making the use of good animal models extremely valuable. One of these animal models is the Flinders Sensitive Line (FSL) of rats, which has face, predictive and constructive validities in relation to human depression. The objective of this study was to quantify the effect of the tryptophan hydroxylase (TPH) activation inhibitor, AGN-2979, on the FSL rats (rats with depression-like behaviour), and compare it to the effect on the Flinders Resistant Line (FRL) of rats used as the control rats. The effect was evaluated by measuring changes in regional serotonin synthesis in the vehicle treated rats (FSL-VEH and FRL-VEH) relative to those measured in the AGN-2979 treated rats (FSL-AGN and FRL-AGN). Regional serotonin synthesis was measured autoradiographically in more than 30 brain regions. The measurements were performed using α-[14C]methyl-l-tryptophan as the tracer. The results indicate that AGN-2979 did not produce a significant reduction of TPH activity in the AGN-2979 group relative to the vehicle group (a reduction would have been observed if there had been an activation of TPH by the experimental setup) in the FSL rats. On the other hand, there was a highly significant reduction of synthesis in the FRL rats treated by AGN-2979, relative to the vehicle group. Together, the results demonstrate that in the FSL rats, AGN-2979 does not affect serotonin synthesis. This suggests that there was no activation of TPH in the FSL rats during the experimental procedure, but such activation did occur in the FRL rats. Because of this finding, it could be hypothesized that TPH in the FSL rats cannot be easily activated. This may contribute to the development of depressive-like symptoms in the FSL rats (“depressed” rats), as they cannot easily modulate their need for elevated amounts of this neurotransmitter, and possibly other neurotransmitters. Further, because these rats represent a very good model of human depression, one can hypothesize that humans who do not have readily activated TPH may be more prone to develop depression.

Chronic buspirone treatment normalizes regional serotonin synthesis in the olfactory bulbectomized rat brain: An autoradiographic study

The effects of chronic buspirone treatments, administered by minipump at doses of 10 and 20 mg/(kg day) for 14 days, on brain 5-HT synthesis in olfactory bulbectomized (OBX) rats were evaluated. The α-[ 14C]methyl- l-tryptophan autoradiographic method was used. We compared the synthesis in the buspirone treated OBX rats (administered either 10 mg/(kg day) (OBX-10) or 20 mg/(kg day) (OBX-20)) to that of the saline treated OBX rats (OBX-SAL), and the sham operated rats (SHX) treated with saline. In addition, OBX-10 rats were compared to SHX rats treated with 10 mg/(kg day) (SHX-10) of buspirone. All treatments were carried out for 14 days. Adult Sprague–Dawley rats were used. Two weeks following the OBX or SHX procedures, the rats were assigned to the OBX-10, OBX-20, OBX-SAL, SHX-10, or SHX-SAL groups, respectively. The 5-HT synthesis rates R (pmol/(g/min)) were calculated from the trapping constant of α-[ 14C]MTrp ( K*; ml/(g min)) and the plasma concentration of the plasma non-protein-bound tryptophan (Cp; pmol/ml) using the lumped constant (LC) measured previously in the rat brain. There was no significant difference in the plasma free or total tryptophan among these groups. The overall synthesis in the OBX-10 group was not statistically different from the OBX-SAL group, but it was different from the OBX-20 and SHX-SAL groups. The OBX-20 rats had an overall significant reduction in 5-HT synthesis, when compared to the OBX-SAL group, but did not differ from the SHX-SAL group, which did not differ from the SHX-10 group. These results suggest that 10 mg/(kg day) of buspirone for 14 days in the OBX rats did not produce a significant alteration in 5-HT synthesis, but 20 mg/(kg day) for 14 days resulted in an overall significant reduction in brain 5-HT synthesis. The latter treatment brought the synthesis to the level found in the sham operated rats, i.e., a normal level. These results suggest that normalization (reduction to the level found in the SHX-SAL rats) of 5-HT synthesis in the OBX requires a greater dose of buspirone (20 mg/(kg day)) than that needed to produce a desensitization of the 5-HT 1A receptors in the sham operated rats (10 mg/(kg day)). This probably indicates that 5-HT 1A receptors have different functionality in the OBX rats than that found in the intact or sham operated rats. Furthermore, our results support the hypothesis that 5-HT 1A receptors mediate the antidepressant-like effect of 5-HT 1A agonists, as the chronic 5-HT 1A agonist treatment in the depression model known to be sensitive to antidepressants resulted in the normalization of 5-HT synthesis.

α-[ 11C]Methyl- l-tryptophan trapping in the orbital and ventral medial prefrontal cortex of suicide attempters

Low serotonin neurotransmission is thought to increase vulnerability to suicidal behavior. To test this hypothesis, we measured brain regional serotonin synthesis, as indexed by PET and α-[ 11C]methyl- l-tryptophan trapping, in 10 patients who had made a high-lethality suicide attempt and 16 healthy controls. Compared to healthy controls, suicide attempters had reduced normalized α-[ 11C]methyl- l-tryptophan trapping in orbital and ventromedial prefrontal cortex. α-[ 11C]Methyl- l-tryptophan trapping in these regions correlated negatively with suicide intent. Low serotonin synthesis in the prefrontal cortex might lower the threshold for suicidal behavior.

Effects of Pentadecapeptide BPC157 on Regional Serotonin Synthesis in the Rat Brain: α-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 α-[ 14C]methyl-L-tryptophan (α-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 μg/kg) administered intraperitoneally 40 min before the α-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 μg/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 desipramine on regional serotonin synthesis in the rat brain: acute and chronic autoradiographic studies

Various studies have implicated the involvement of noradrenaline (NA) and/or serotonin (5-hydroxytryptamine (5-HT)) in the pathogenesis and treatment of depression. The aim of the present study was to investigate the effects of acute and 7 days of administration of desipramine, a NA re-uptake inhibitor, on the rate of 5-HT synthesis in the rat brain. The study was done by an autoradiographic method using α-[ 14 C ]-methyl- l-tryptophan as a tracer. The acute (10 mg/kg, i.p., 2 h before i.v. infusion of the tracer) or 7 days of desipramine (10 mg/kg per day, i.p.) did not affect plasma tryptophan (Trp) concentrations, as compared to control (saline treated) rats. Acute treatment with desipramine decreased the rate of 5-HT synthesis in the brain regions that contain 5-HT cell bodies between 19 and 28%, and increased the rate of 5-HT synthesis in the majority of areas containing 5-HT terminals between 21 and 65%. In contrast to the acute treatment, a 7-day administration increased 5-HT synthesis rates in the dorsal raphe (24%), but decreased it in raphe magnus (35%), superior olive (45%), caudate (31%), superior (38%) and inferior (53%) colliculus, and in the auditory cortex (35%). This suggests that the effect of desipramine on 5-HT synthesis rate is time-dependent and differs in the cell bodies and structures containing 5-HT nerve terminals.

Effects of serotine receptors agonists, TFMPP and CGS12066B, on regional serotonin synthesis in the rat brain: an autoradiographic study

The effects of acute and repeat administration of the serotonin (5-HT)(1) agonists TFMPP [N -(3-trifluoromethyl)phenylpiperazine hydrochloride] and CGS12066B [7-trifluoromethyl-4- (4-methyl-1-piperazinyl)pyrrolo[1,2-a ]-quinoxaline dimaleate] were evaluated on 5-HT synthesis rates using the alpha-[(14) C]methyl-l-tryptophan (alpha-MTrp) autoradiographic method. In the acute treatment study, TFMPP (10 mg/kg) and CGS12066B (5 mg/kg) were injected intraperitoneally 30 min before an alpha-MTrp injection. In an acute study TFMPP reduced overall brain 5-HT synthesis, in the dorsal and median raphe, and in almost all of their projection areas, with the exception of the parietal, sensory-motor, and frontal cortices, the accumbens nucleus, and the caudate. Acute CGS12066B treatment did not have overall significant effect, but the rates did decrease in the cell body areas of 5-HT neurons. In a 7-day treatment with TFMPP (10 mg/kg/day) or CGS12066B (5 mg/kg/day), the 5-HT synthesis rates (24 h after last dose) decrease, with both compounds, in almost all of the nerve terminal structures. TFMPP reduced the synthesis in the dorsal and median raphe, while CGS12066B reduced it only in the dorsal raphe. This data suggests that after a 7-day treatment with TFMPP and CGS12066B, the rate of 5-HT synthesis in the dorsal raphe is restored and is reduced in many projection areas. The observed effects in the 7-day treatment could also be related to actions through the postsynaptic 5-HT(1B) sites and/or other 5-HT receptors since this compounds have limited selectivity.

Effects of selective 5-HT 1A receptor antagonists on regional serotonin synthesis in the rat brain: An autoradiographic study with α-[ 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 α-[ 14C]methyl- l-tryptophan (α-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-HT 1A 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 net unidirectional uptake of alpha-[14c]methyl-L-tryptophan (alpha-MTrp) and its correlation with regional serotonin synthesis, tryptophan incorporation into proteins, and permeability surface area products of tryptophan and alpha-MTrp.

The uptake and trapping constants for labeled tryptophan (Trp) via the serotonin (5-hydroxytryptamine; 5-HT) metabolic pathway and for the incorporation of Trp into proteins, and alpha-[14C]methyl-L-tryptophan (alpha-MTrp) were measured. Measurements were done in rats treated with either saline or probenecid (200 mg/kg). In addition, the blood-brain barrier (BBB) permeability surface area products for Trp (PS(T)) and alpha-MTrp (PSalpha) were measured in normal rats. The results suggest that, in both groups of rats, there is a highly significant correlation (p < 0.05; Pearson Product Moment Correlation (PPMC) between the brain uptake and trapping constants for alpha-MTrp and those of Trp via the 5-HT metabolic pathway, but there is no significant correlation (p > 0.05; PPMC) between either of these constants and the PS products of either compound. There is also no significant correlation (p > 0.05; PPMC) between the constant for the Trp incorporation into proteins with any of the other parameters. For all parameters, except Trp incorporation into proteins (alpha-MTrp is not incorporated into proteins), there was a highly significant correlation (p < 0.001) between the quantities measured for Trp and alpha-MTrp. The data presented here strongly suggests that the brain uptake and trapping of alpha-MTrp relates to brain 5-HT synthesis, and does not relate to the BBB transport or protein incorporation of Trp. On the basis of these results, as well as those previously reported, we concluded that trapping (unidirectional uptake) of alpha-MTrp can be converted to the 5-HT synthesis rates in the brain. From this also follows that labeled alpha-MTrp is a good tracer for in vivo evaluation of the brain 5-HT synthesis.

Brain regional serotonin synthesis following adaptation to repeated restraint.

A single 2 h episode of restraint stress decreased food intake and growth rate of rats. These deficits were not observed after five restraint periods of 2 h a day, suggesting that adaptation occurred. An acute challenge with 2 h restraint increased 5-hydroxytryptamine (5-HT) synthesis rate in the cortex, hypothalamus, midbrain and hindbrain of previously unrestrained rats, but not those adapted to 5 days of 2 h daily restraint. Hippocampal and striatal 5-HT synthesis was not increased significantly by 2 h restraint in previously unrestrained rats but was increased and decreased, respectively, in rats exposed to five 2 h daily restraints, when they were restrained on the sixth day. The findings suggest an important role of 5-HT particularly in the hippocampus, in adaptation to stress.