The tryptophan hydroxylase activation inhibitor, AGN-2979, decreases regional 5-HT synthesis in the rat brain measured with α-[14C]methyl-l-tryptophan: An autoradiographic study

Hasegawa, Shu; Kanemaru, Kazuya; Gittos, Maurice W.; Dikšić, Mirko

doi:10.1016/j.brainresbull.2005.07.009

Cited by 10 publications

(17 citation statements)

References 45 publications

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“…A possible mechanism for the reversible kinetics can be derived from the observation that the rate constant for the It seems reasonable that the measures obtained with these PET tracers should be different as the tracers target different enzymes that differ in their enzyme activity in the brain (Ichiyama et al, 1968). In recent autoradiographic studies, pharmacological inhibition of tryptophan hydroxylase with p-chlorophenylalanine or AGN-2979 decreased the unidirectional trapping of [ 14 C]AMT (Hasegawa et al, 2005;Tohyama et al, 2002). In rats (Lindner et al, 1997) and rhesus monkeys (Lundquist et al, 2006), pharmacological inhibition of AADC by NSD1015 decreased the trapping rate constant of [ 11 C]HTP.…”

Section: Discussionmentioning

confidence: 99%

5-Hydroxy-l-[β-¹¹C]tryptophan versus α-[¹¹C]Methyl-l-tryptophan for Positron Emission Tomography Imaging of Serotonin Synthesis Capacity in the Rhesus Monkey Brain

Lundquist

Hartvig

Blomquist

et al. 2006

J Cereb Blood Flow Metab

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The purpose of this study was to compare two positron emission tomography (PET) tracers that were developed to follow serotonin (5HT) synthesis by performing sequential PET scanning of the same rhesus monkey (n = 4) on the same day. a-[ 11 C]Methyl-L-tryptophan ([ 11 C]AMT) and 5-Hydroxy-L-[b-11 C]tryptophan ([ 11 C]HTP) are substrates in the first and second enzymatic steps, respectively, in the biosynthesis of 5HT. Regional net accumulation rate constants were derived from kinetic (two-tissue compartment model with irreversible tracer trapping) and graphic (Patlak) analyses, using the arterial plasma concentrations as input. The kinetic data analysis showed that the rate constant for the transfer of [ 11 C]HTP into the brain (K 1) was higher than that for [ 11 C]AMT in the striatum and thalamus but was similar in other brain regions. The rate constant for tracer trapping (k 3) was also higher for [ 11 C]HTP than for [ 11 C]AMT in the striatum (0.04660.024 versus 0.01960.006 min À1) and thalamus (0.03960.013 versus 0.01660.007 min À1). In agreement with previously reported regional HTP accumulation rates, the net accumulation rate constant (K acc) for [ 11 C]HTP was also higher in these regions than in other brain regions; this is in contrast to the uniform distribution of [ 11 C]AMT K acc values. This suggests that the regional net accumulation rates obtained with these two PET tracers will be of different magnitude, which might be related to the activity of each targeted enzyme.

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Section: Discussionmentioning

confidence: 99%

5-Hydroxy-l-[β-¹¹C]tryptophan versus α-[¹¹C]Methyl-l-tryptophan for Positron Emission Tomography Imaging of Serotonin Synthesis Capacity in the Rhesus Monkey Brain

Lundquist

Hartvig

Blomquist

et al. 2006

J Cereb Blood Flow Metab

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“…2) Is the activation of TPH in the FSL rats different from that in the FRL rats? 3) How does the activation differ in these two strains of rats from that reported previously (historic controls) in normal SPD rats (Hasegawa et al 2005), and are the effects different in different brain regions?…”

Section: Introductionmentioning

confidence: 88%

“…We recently demonstrated that in normal Sprague-Dawley (SPD) rats, an acute treatment of AGN 2979 produces a reduction in 5-HT synthesis relative to the synthesis in vehicle treated rats (Hasegawa et al 2005). This observation was interpreted as AGN-2979 preventing TPH activation produced by the experimental setup ( e.g.…”

Section: Introductionmentioning

confidence: 99%

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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

Kanemaru

Nishi

Dikšić

2009

Neurochemistry International

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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 thirty brain regions. The measurements were performed using α-[ 14 C]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 set up) 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 hypothesised 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 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

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“…Ironically, its development as an antidepressant was regarded as potentially dangerous because, according to the 5-HT deficiency theory of depression, its ability to decrease 5-HT transmission would have exacerbated the disorder. AGN 2979 is an effective anti-stress agent, decreasing stress-related increases in regional 5-HT synthesis in rat brains by 12-35% [Hasegawa et al, 2005], and has been shown to exert rapid (1 week) antidepressantlike effects in rats [Gittos and Papp, 2001]. In the clinic, tested as an antidepressant at a dose level of 100-200 mg bid, six of the seven treated, hospitalized, patients improved by 19-39% at the end of the first week [Clerc et al, 1986].…”

Section: Affective Disorders Diminished By Antistress Agentsmentioning

confidence: 99%

Toward a better understanding of depression and anxiety: the involvement of stress and tryptophan hydroxylase activation

Gittos¹

2006

Drug Development Research

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Tryptophan hydroxylase (TPH) has been implicated as the key enzyme involved in the etiology of the affective disorders, anxiety and depression. In addition to its activation by stress, TPH is also activated by the amino-acid decarboxylase inhibitor, NSD 1015, which is widely used for the determination of serotonin turnover. The blockade of this activation by the established antidepressants provides a new, distinct concept to account for the beneficial activity of these compounds. The blockade of the stress-induced activation of TPH by the benzodiazepine, diazepam, is consistent with its anxiolytic activity involving TPH activation inhibition. In support of the concept, a selective TPH activation inhibitor, AGN 2979, has been reported to exert both powerful antidepressant and anxiolytic effects in the clinic, with a notable lack of the side effects associated with transmitter reuptake inhibition and benzodiazepine receptor interactions. Drug Dev. Res. 67:801-805, 2006.

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The tryptophan hydroxylase activation inhibitor, AGN-2979, decreases regional 5-HT synthesis in the rat brain measured with α-[14C]methyl-l-tryptophan: An autoradiographic study

Cited by 10 publications

References 45 publications

5-Hydroxy-l-[β-¹¹C]tryptophan versus α-[¹¹C]Methyl-l-tryptophan for Positron Emission Tomography Imaging of Serotonin Synthesis Capacity in the Rhesus Monkey Brain

5-Hydroxy-l-[β-¹¹C]tryptophan versus α-[¹¹C]Methyl-l-tryptophan for Positron Emission Tomography Imaging of Serotonin Synthesis Capacity in the Rhesus Monkey Brain

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

Toward a better understanding of depression and anxiety: the involvement of stress and tryptophan hydroxylase activation

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The tryptophan hydroxylase activation inhibitor, AGN-2979, decreases regional 5-HT synthesis in the rat brain measured with α-[14C]methyl-l-tryptophan: An autoradiographic study

Cited by 10 publications

References 45 publications

5-Hydroxy-l-[β-11C]tryptophan versus α-[11C]Methyl-l-tryptophan for Positron Emission Tomography Imaging of Serotonin Synthesis Capacity in the Rhesus Monkey Brain

5-Hydroxy-l-[β-11C]tryptophan versus α-[11C]Methyl-l-tryptophan for Positron Emission Tomography Imaging of Serotonin Synthesis Capacity in the Rhesus Monkey Brain

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

Toward a better understanding of depression and anxiety: the involvement of stress and tryptophan hydroxylase activation

Contact Info

Product

Resources

About

5-Hydroxy-l-[β-¹¹C]tryptophan versus α-[¹¹C]Methyl-l-tryptophan for Positron Emission Tomography Imaging of Serotonin Synthesis Capacity in the Rhesus Monkey Brain

5-Hydroxy-l-[β-¹¹C]tryptophan versus α-[¹¹C]Methyl-l-tryptophan for Positron Emission Tomography Imaging of Serotonin Synthesis Capacity in the Rhesus Monkey Brain