Elsevier

Biological Psychiatry

Volume 52, Issue 7, 1 October 2002, Pages 759-763
Biological Psychiatry

Original article
Sex differences in striatal presynaptic dopamine synthesis capacity in healthy subjects

https://doi.org/10.1016/S0006-3223(02)01369-0Get rights and content

Abstract

Background

There are sex differences in the clinical features of several neuropsychiatric illnesses associated with dopamine dysfunction. The effects of sex on brain dopaminergic function have been sparsely studied in human subjects using modern imaging techniques. We have previously reported that the apparent affinity of [11C]raclopride for striatal D2 dopamine receptors in vivo is lower in women than in men, whereas D2 receptor density is not different. This finding indirectly suggests that women have a higher synaptic concentration of dopamine in the striatum. We explored further the basis of this phenomenon in an independent study and hypothesized that striatal presynaptic dopamine synthesis capacity would also be elevated in women.

Methods

A total of 23 healthy men and 12 healthy women (age range 20–60 years) were studied using positron emission tomography and [18F]fluorodopa.

Results

Women had significantly higher striatal [18F]fluorodopa uptake (Ki values) than men. The difference was more marked in the caudate (+26%) than in the putamen (+12%). In addition, there was a negative correlation between striatal [18F]fluorodopa Ki values and age in men but not in women.

Conclusions

The results further substantiate sex differences in striatal dopaminergic function in humans. This finding may be associated with sex differences in vulnerability and clinical course of neuropsychiatric disorders with dopaminergic dysregulation, e.g., schizophrenia, alcohol dependence, and Parkinson’s disease.

Introduction

Gex differences in the brain dopaminergic system have been extensively studied in animals (Becker 1999), but much less is known about the effects of gender on the brain dopaminergic system in humans. Sex affects the vulnerability for many neurologic and psychiatric disorders involving dopamine. Men have a higher risk than women do for Parkinson’s disease (Kompoliti 1999) and alcohol and substance abuse (Seeman 1997). The onset of schizophrenia occurs on average 3–5 years later in women than in men because women have another peak of onset in their mid-to-late forties Häfner et al (1998), Salem and Kring (1998). Although several other factors associated with gender may be responsible for these epidemiologic differences, a differently regulated dopaminergic system is an interesting candidate.

We recently reported a sex difference in the in vivo affinity (Kd) of [11C]raclopride for striatal D2 dopamine receptors in healthy human subjects (Pohjalainen et al 1998). Our results suggest that women have a higher synaptic concentration of dopamine in the striatum, competing with [11C]raclopride binding. In addition, while investigating the uptake of radiolabeled dopamine precursor [18F]fluorodopa (FDOPA), an index of presynaptic dopamine synthesis in adult patients with attention deficit hyperactivity disorder, Ernst et al (1998) noticed that female subjects in the patient and control groups had higher striatum-to-cortex ratios than male subjects. Furthermore, dopamine transporter binding has recently been reported to be higher in healthy women than in men, suggesting that the density of dopaminergic nerve terminals might be higher in women Lavalaye et al (2000), Mozley et al (2001). To test further the hypothesis of higher presynaptic dopamine function in women, we studied striatal [18F]FDOPA uptake with positron emission tomography (PET) in 23 healthy men and 12 healthy women.

Section snippets

Subjects

The study was approved by the Ethical Committee of Turku University and Turku Central Hospital and was conducted according to the Declaration of Helsinki. After a complete description of the study to the subjects, a written informed consent was obtained. Thirty-five healthy nonsmoking volunteers with no history of mental or neurologic illness or alcohol or drug abuse were recruited. The groups consisted of 23 men and 12 women with similar age, i.e., 36.2 ± 11.4 and 35.9 ± 10.6 years in the male

Positron Emission Tomography (PET)

Positron emission tomography scans for [18F]FDOPA were performed as described previously (Hietala et al 1999) using a whole-body PET scanner (ECAT 931/08–12, Computer Technology and Imaging (CTI), Knoxville, TN) with 15 slices. On the morning of the study, subjects were allowed to eat a light, protein-poor breakfast to minimize plasma levels of large neutral amino acids. Ninety minutes before the scan, 100 mg of peripheral dopa decarboxylase inhibitor carbidopa (Orion Pharma, Finland) was given

Statistics

Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) 10.0 for Windows software (SPSS, Chicago, IL). Gender differences were studied with an independent samples t test and univariate analysis of variance using age as a covariate. Equality of variances between gender groups was studied with Levene’s test. Correlations between age and [18F]FDOPA uptake were studied with Pearson’s Correlation Analysis. Statistical differences between the slopes for the

Sex and [18F]FDOPA

On average, women had 26% higher [18F]FDOPA Ki values in the caudate than men (0.0108 ± 0.0024 and 0.0086 ± 0.0021, respectively, means ± SD, t = 2.915, p = .006, independent samples t test), whereas the difference was somewhat less marked in the putamen (0.0127 ± 0.0023 and 0.0113 ± 0.0018, respectively, means ± SD, t = 1.995, p = .054). The [18F]FDOPA Ki value was consistently higher in women in both hemispheres in the caudate and putamen, but the difference was more pronounced in the right

Discussion

There are two main findings in the present study: 1) healthy premenopausal women have a higher striatal presynaptic dopamine synthesis capacity than healthy men of similar age; and 2) the effect of age on striatal [18F]FDOPA Ki values is different in healthy men and women, leading to a relative decrease in dopamine activity with age in men but not in women. In addition, the sex difference in average [18F]FDOPA Ki values seems to be more marked in the caudate, whereas the difference in the

Acknowledgements

AL is currently affiliated with Howard Hughes Medical Institute Laboratories, Department of Cell Biology, Duke University Medical Center, Durham, North Carolina.

This work was supported by the Academy of Finland.

The authors thank staff members in the Turku PET Centre and Department of Radiology, Turku University Central Hospital, for their assistance.

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