Elsevier

NeuroImage

Volume 33, Issue 3, 15 November 2006, Pages 815-824
NeuroImage

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

https://doi.org/10.1016/j.neuroimage.2006.08.004Get rights and content

Abstract

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 α-[11C]methyl-l-tryptophan (α-[11C]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 α-[11C]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.

Introduction

Both direct and indirect measures suggest that there are gender differences in serotonin (5-HT) neurotransmission. For example, post-mortem and in vivo functional neuroimaging studies suggest gender differences in 5-HT receptor densities (Arango et al., 1995, Biver et al., 1996, Meltzer et al., 2001, Parsey et al., 2002) and imipramine binding (Arato et al., 1991). Pharmaconeuroendocrine studies suggest that prolactin responses to fenfluramine (McBride et al., 1990), tryptophan (Delgado et al., 1989, Deakin et al., 1990), m-cholorophenylpiperazine (Kahn et al., 1991), and buspirone (Meltzer and Maes, 1994) are greater in women than in men. Studies of cerebrospinal fluid (CSF) concentrations of the 5-HT metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) raise the possibility that some of these differences may be related to gender differences in brain 5-HT synthesis and, by implication, the differential availability of the transmitter for release into the synaptic cleft. However, these studies have yielded inconsistent results, with increased, decreased, and no difference in 5-HIAA levels being reported (Sjostrom and Roos, 1972, Asberg et al., 1973, Agren et al., 1986, Young et al., 1980, Bowden et al., 1981, von Knorring et al., 1986, Blennow et al., 1993).

Because CSF 5-HIAA measures reflect other processes, in addition to 5-HT synthesis, an alternative approach is to use positron emission tomography (PET) and the tracer α-[11C]methyl-l-tryptophan (α-[11C]MTrp). Validation studies suggest that α-[11C]MTrp trapping rate constant provides a good in vivo index of brain regional 5-HT synthesis (Diksic et al., 1990, Nagahiro et al., 1990, Diksic et al., 1991, Diksic, 2001, Vanier et al., 1995, Muzik et al., 1997, Chugani et al., 1998, Leyton et al., 2005). In α-[11C]MTrp studies, gender-related differences have been seen in healthy controls (Nishizawa et al., 1997, Chugani et al., 1998, Okazawa et al., 2000) and in patients with borderline personality disorder (Leyton et al., 2001), irritable bowel syndrome (IBS) (Nakai et al., 2003, Nakai et al., 2005), and major depression (Rosa-Neto et al., 2004). There have been some criticisms of the α-[11C]MTrp PET method and those were addressed in our review articles (Diksic and Young, 2001, Diksic, 2001), and subsequently additional validation data have been published (Tohyama et al., 2002, Nishikawa et al., 2005, Leyton et al., 2005).

The lower rate of 5-HT synthesis, as calculated from trapping of α-[11C]MTrp, initially seen in healthy women may have been driven in part by differences in the plasma concentrations of the endogenous 5-HT precursor, the essential amino acid tryptophan (Trp) (Nishizawa et al., 1997). Gender differences in brain 5-HT synthesis, as deduced from absolute brain α-[11C]MTrp trapping constants (μl/g/min), have also been reported by a second group (Chugani et al., 1998). However, the latter results may also have been affected by differences in plasma Trp and/or the plasma free fraction of Trp as the absolute α-[11C]MTrp trapping constants were reported without normalization or information about plasma Trp levels. In rats, there is a highly significant (p < 0.001) correlation between α-MTrp and Trp binding to plasma proteins (Diksic et al., unpublished observation). This factor is incorporated into K* (trapping constant used as a proxy of 5-HT synthesis) as calculated from the model equations (Diksic et al., 1991). Given these issues, we report here PET α-[11C]MTrp data from a substantially larger group of healthy men and women using Statistical Parametric Mapping (SPM) analyses with proportional scaling to factor out the influence of plasma Trp as well as the plasma free fractions of Trp and the tracer. In addition, this normalization procedure would factor out any possible effects from differences in apparent Km between different subjects because through normalization they are cancelled out.

Section snippets

Subjects

Twenty-eight healthy female (mean age ± standard deviation (SD); 33.2 ± 17.2 years; range of 19 to 80 years) and thirty-one healthy male (29.8 ± 12.8 years; range of 19 to 80 years) volunteers were studied. All of the subjects underwent a detailed physical examination and a screening through laboratory tests. This procedure would exclude from this study subjects with a medical condition. Prior to each PET measurement, a sample of urine was obtained to screen for drugs that could potentially interact

Results

Relative rates of 5-HT synthesis, as indexed by proportionally normalized α-[11C]MTrp trapping rate constants, were significantly lower in the female subjects than the male subjects, in the multiple cortical regions (Table 1, Fig. 1, Fig. 2, Fig. 3): the left middle frontal gyrus, the bilateral inferior frontal gyrus, the left precentral gyrus, the left supramarginal gyrus, the bilateral inferior parietal lobule, the left superior temporal gyrus, the bilateral posterior cingulate gyrus, and the

Discussion

The primary finding in the present study was evidence, obtained by the PET α-[11C]MTrp method, that a normalized index of brain 5-HT synthesis measured by trapping of α-[11C]MTrp in the cerebral cortex of healthy humans is lower in women than in men. These observations support our earlier preliminary evidence of lower 5-HT synthesis measured by trapping of α-[11C]MTrp in healthy women than men (Nishizawa et al., 1997) and suggest that the differences are not an artifact of lower plasma levels

Conclusion

The present study suggests that normalized rates of 5-HT synthesis as measured by trapping of α-[11C]MTrp are lower in females than in males in multiple regions of the cerebral cortex, whereas there was no region in which this parameter was higher in females. In addition, greater differences were found on the left side of the brain. One implication is that this gender difference may contribute to some behavioral differences between men and women, perhaps accounting, in part, for the

Acknowledgments

The research was supported in part by grants from the NIH, CIHR, and FRSQ. We would like to acknowledge the dedicated technical support from the Radiochemistry-Cyclotron and Positron Emission Tomography Units. M.D. is a Killam Scholar at the Montreal Neurological Institute, McGill University, C.B. holds a Chercheur National Award and M.L. holds a Chercheur Boursier from FRSQ.

References (71)

  • R.S. Kahn et al.

    Pituitary hormone responses to meta-chlorophenylpiperazine in panic disorder and healthy control subjects

    Psychiatry Res.

    (1991)
  • G.A. Kennett et al.

    Female rats are more vulnerable than males in an animal model of depression: the possible role of serotonin

    Brain Res.

    (1986)
  • R.C. Kessler et al.

    Sex and depression in the National Comorbidity Survey. I: Lifetime prevalence, chronicity and recurrence

    J. Affect. Disord.

    (1993)
  • R.C. Kessler et al.

    Sex and depression in the National Comorbidity Survey. II: Cohort effects

    J. Affect. Disord.

    (1994)
  • P.A. McBride et al.

    Effects of age and gender on CNS serotonergic responsivity in normal adults

    Biol. Psychiatry

    (1990)
  • H.Y. Meltzer et al.

    Effects of buspirone on plasma prolactin and cortisol levels in major depressed and normal subjects

    Biol. Psychiatry

    (1994)
  • C. Meltzer et al.

    Gender-specific aging effects on the serotonin 1A receptor

    Brain Res.

    (2001)
  • S. Mzengeza et al.

    Asymmetric radiosynthesis of alpha-[11C]methyl-l-tryptophan for PET studies

    Nucl. Med. Biol.

    (1995)
  • M. Nishikawa et al.

    Increasing the blood oxygen tensions increases an index of 5-HT synthesis in human brain as measured using α-[11C]methyl-l-tryptophan and positron emission tomography

    Neurochem. Int.

    (2005)
  • R.V. Parsey et al.

    Effects of sex, age, and aggressive traits in man on brain serotonin 5-HT1A receptor binding potential measured by PET using [C-11]WAY-100635

    Brain Res.

    (2002)
  • H.S. Stock et al.

    Gender and gonadal hormone effects in the olfactory bulbectomy animal model of depression

    Pharmacol. Biochem. Behav.

    (2000)
  • Y. Tohyama et al.

    The inhibition of tryptophan hydroxylase, and not protein synthesis, reduces the brain trapping of α-methyl-l-tryptophan: an autoradiographic study

    Neurochem. Int.

    (2002)
  • N. Tzourio-Mazoyer et al.

    Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain

    NeuroImage

    (2002)
  • S.N. Young et al.

    The role of serotonin in human mood and social interaction. Insight from altered tryptophan levels

    Pharmacol. Biochem. Behav.

    (2002)
  • M. Arato et al.

    Serotonergic interhemispheric asymmetry: gender difference in the orbital cortex

    Acta Psychiatr. Scand.

    (1991)
  • M. Asberg et al.

    Indoleamine metabolites in the cerebrospinal fluid of depressed patients before and during treatment with nortriptyline

    Clin. Pharmacol. Ther.

    (1973)
  • J.A. Aston et al.

    Positron emission tomography partial volume correction: estimation and algorithms

    J. Cereb. Blood Flow Metab.

    (2002)
  • C. Benkelfat et al.

    The validity of the PET/α-[11C]methyl-l-tryptophan method for measuring rates of serotonin synthesis in the human brain

    Neuropsychopharmacology

    (1999)
  • G. Blomqvist

    On the construction of functional maps in positron emission tomography

    J. Cereb. Blood Flow Metab.

    (1984)
  • D.L. Bloxam et al.

    A study of proposed determinants of brain tryptophan concentration in rats after portocaval anastomosis or sham operation

    J. Neurochem.

    (1978)
  • C.L. Bowden et al.

    Pretreatment amine neurotransmitter system interrelationships in depression

    Psychopharmacol. Bull.

    (1981)
  • S. Chevalier et al.

    Influence of adiposity in the blunted whole-body protein anabolic response to insulin with aging

    J. Gerontol., Ser. A, Biol. Sci. Med. Sci.

    (2006)
  • D.C. Chugani et al.

    Human brain serotonin synthesis capacity measured in vivo with alpha-[C-11]methyl-l-tryptophan

    Synapse

    (1998)
  • D.L. Collins et al.

    Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space

    J. Comput. Assist. Tomogr.

    (1994)
  • J.F. Deakin et al.

    A neuroendocrine study of 5HT function in depression: evidence for biological mechanisms of endogenous and psychosocial causation

    Psychopharmacology (Berlin)

    (1990)
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    Presented in part at the Society for Neuroscience 34th Annual Meeting, October 23–26, 2004, San Diego, CA.

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