Differences between males and females in rates of serotonin synthesis in human brain

Abstract

Rates of serotonin synthesis were measured in the human brain using positron emission tomography. The sensitivity of the method is indicated by the fact that measurements are possible even after a substantial lowering of synthesis induced by acute tryptophan depletion. Unlike serotonin levels in human brain, which vary greatly in different brain areas, rates of synthesis of the indolamine are rather uniform throughout the brain. The mean rate of synthesis in normal males was found to be 52% higher than in normal females; this marked difference may be a factor relevant to the lower incidence of major unipolar depression in males. Low brain serotonin (5-HT) levels or function have been implicated in various types of psychopathology, including depression, suicide, aggression, anxiety, and bulimia (for reviews see refs. 1-3). Until recently, the principal methods for studying serotonin metabolism in human brain were determination of the metabolite of serotonin 5-hydroxyindole-3-acetic acid (5-HIAA) in cerebrospinal fluid (CSF) and postmortem measurements of brain serotonin and 5-HIAA. Both methods have limitations. In particular, neither provides a direct measure of serotonin synthesis in the living brain. Recently, a method for measuring serotonin synthesis in the brain of living mammals has been developed (4-5) and tested successfully in dogs (6). The method uses positron emission tomography (PET) and ␣-[11 C]methyl-L-tryptophan as a tracer. The tracer is converted in part to ␣-[11 C]methylserotonin, which accumulates in serotonin neurons, because it is not a substrate for monoamine oxidase and does not cross the bloodbrain barrier.We report here in vivo measurements of serotonin synthesis in the brain of healthy volunteers. Both male and female subjects were studied because CSF studies suggest that the rate of brain serotonin metabolism is higher in females than in males (7-8), and because the incidence of major unipolar depression is higher in women (9). We measured rates of serotonin synthesis under two conditions: at baseline and after acute tryptophan depletion (ATD). For ATD, subjects ingest a tryptophan-free mixture of all the essential amino acids. This induces protein synthesis, which incorporates body stores of free tryptophan into protein, thus reducing the level of this amino acid in tissues, including brain (10). Because tryptophan is the precursor of serotonin, its reduction is thought to lower the rate of serotonin synthesis in brain (11-12). ATD was used in the present study for several reasons. First, low serotonin levels have been proposed to relate to various types of psychopathology (for reviews see refs. 1-3), so any useful method of in vivo measurements of the serotonin synthesis rate must have a demonstrated capability for measuring low rates of serotonin synthesis. Second, ATD induces a transient reappearance of depressive symptoms in patients under treatment with antidepressants (13). Moreover, ATD also produces a mild lowering of mood in normal subjects with a family history of de...

Sex Differences in the Regulation of Serotonergic Transmission and Behavior in 5-HT Receptor Knockout Mice

“…Lower rates of 5-HT synthesis have been reported in human females (Nishizawa et al, 1997). Female rats showed lower baseline hypothalamic 5-HT levels and a reduced response to paroxetine or fenfluramine during estrous than males (Gundlah et al, 1998).…”

“…Sex differences in the 5-HT system have long been demonstrated in rodents and humans (Nishizawa et al, 1997;McEwen et al, 1998). If the increased baseline hippocampal 5-HT efflux in female 5-HT 1B receptor mutant mice were extended to other brain regions, this finding would suggest the existence of a broader range of phenotypic and functional differences that are sex-dependent.…”

“…Alterations in the tone of serotonin (5-HT) transmission may be a major contributor to gender disparity (Akiskal, 1989;Pfaff, 1997;Bagdy, 1998;Joffe and Cohen, 1998), and women have shown decreased whole brain 5-HT synthesis (Nishizawa et al, 1997), increased cerebrospinal fluid levels of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA), and decreased 5-HT 2 receptor binding in specific brain regions (Biver et al, 1996) when compared to men. The impact of 5-HT-related gene polymorphisms of serotonergic function also varies between sexes.…”

“…Sex differences in the 5-HT system have been demonstrated in rodents and humans (for reviews, see Nishizawa et al, 1997;McEwen et al, 1998). The current behavioral and microdialysis studies demonstrate how 5-HT regulation in mice with a targeted genetic dysfunction can lead to sexspecific outcomes.…”

Positron Emission Tomography of Regional Brain Metabolic Responses to a Serotonergic Challenge in Major Depressive Disorder with and without Borderline Personality Disorder

“…However, regional CMRglu differences between men and women have not been consistently reported (Baxter Jr et al, 1989;Miura et al, 1990). Potential gender differences may exist in FEN activation of CMRglu as there is evidence of gender effects in serotonergic brain function, and rates of serotonin synthesis have been shown to differ by gender (Nishizawa et al, 1997). Moreover, gonadal hormones are known to affect serotonergic responsivity.…”