Sex differences in the serotonin 1A receptor and serotonin transporter binding in the human brain measured by PET

Abstract

Women and men differ in serotonin associated psychiatric conditions, such as depression, anxiety and suicide. Despite this, very few studies focus on sex differences in the serotonin system. Of the biomarkers in the serotonin system, serotonin_1A (5-HT_1A) receptor is implicated in depression, and anxiety and serotonin transporter (5-HTT) is a target for selective serotonin reuptake inhibitors, psychotropic drugs used in the treatment of these disorders. The objective of the present study was to study sex related differences in the 5-HT_1A receptor and 5-HTT binding potentials (BP_NDs) in healthy humans, in vivo. Positron emission tomography and selective radioligands [¹¹C]WAY100635 and [¹¹C]MADAM were used to evaluate binding potentials for 5-HT_1A receptors (14 women and 14 men) and 5-HTT (8 women and 10 men). The binding potentials were estimated both on the level of anatomical regions and voxel wise, derived by the simplified reference tissue model and wavelet/Logan plot parametric image techniques respectively.

Compared to men, women had significantly higher 5-HT_1A receptor and lower 5-HTT binding potentials in a wide array of cortical and subcortical brain regions. In women, there was a positive correlation between 5-HT_1A receptor and 5-HTT binding potentials for the region of hippocampus. Sex differences in 5-HT_1A receptor and 5-HTT BP_ND may reflect biological distinctions in the serotonin system contributing to sex differences in the prevalence of psychiatric disorders such as depression and anxiety. The result of the present study may help in understanding sex differences in drug treatment responses to drugs affecting the serotonin system.

Introduction

A growing body of evidence suggests major differences in brain structure, function and neurochemistry between healthy women and men (Cosgrove et al., 2007). Women and men differ in serotonin associated psychiatric conditions, such as depression, anxiety and suicide (Gorman, 2006, Weiss et al., 2006). Epidemiological studies have reported two times higher rates of depression in women (8%) compared to men (4%) (Kessler et al., 1993). Similarly, it has been shown that women more often than men suffer from anxiety disorders (Pigott, 1999) and that the sexes differ in suicidal behavior (Lewinsohn et al., 2001).

The mechanism underlying these striking sex differences is poorly understood. An increasing amount of animal and human experimental data suggests a substantial influence of sex on the serotonin system function. Sexual dimorphisms in the serotonin system were first suggested in the early 1960s by studies using animal models (Kato, 1960). Central serotonin levels as well as cerebrospinal fluid (CSF) concentrations of the serotonin metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) were found to be higher in female compared to male rats (Rosecrans, 1970). In humans, postmortem studies have revealed significant differences between women and men in the amounts of 5-HIAA and the cathecholamine metabolite homovanilic acid (HVA) in brain tissue (Gottfries et al., 1974). However, these studies have certain limitations in providing direct assessments of brain serotonin in the living human brain. Recently, an in vivo investigation with positron emission tomography (PET) and α-[¹¹C]methyl-l-tryptophan (α-[¹¹C]MTrp) used as an index of serotonin synthesis, showed significant differences between sexes, suggesting lower trapping of α-[¹¹C]MTrp in women compared to men (Sakai et al., 2006).

Among proteins of the serotonin system, the 5-HT_1A-receptor subtype is implicated in depression and anxiety, and 5-HTT is a target for selective serotonin reuptake inhibitors (SSRI), which are drugs used for the treatment of these psychiatric disorders. Both 5-HT_1A receptor and 5-HTT are possible to quantify in vivo, in humans by using high-resolution PET and suitable radioligands. The selective radioligands [¹¹C]WAY100635 for 5-HT_1A and [¹¹C]MADAM for 5-HTT were previously developed at our laboratory (Farde et al., 1998, Halldin et al., 2005). The [¹¹C]WAY100635 labels both low and high-affinity 5-HT_1A receptors, and the [¹¹C]MADAM is a new advance in brain imaging with high selectivity and specificity for 5-HTT. One example of this advancement is the signal-to-noise ratio that has been reported by Frankle et al. (2004) to be higher for [¹¹C]-DASB than the previously rather widely used 5-HTT radioligand [¹¹C]-McN552. Interestingly, the comparison data from the study of Lundberg et al. (2005) with those of Frankle et al. (2004) indicated even higher signal-to-noise ratios for [¹¹C]MADAM (2–3 times higher BP_indirect in most regions) when compared with [¹¹C]-DASB. Moreover, test–retest measurements of [¹¹C]MADAM binding to the 5-HTT has shown good to excellent reliability by using the simplified reference tissue model (SRTM) (Lundberg et al., 2006), suggesting the suitability of simplified approaches for application in clinical studies such as the present study.

A few PET studies have examined the effects of sex on 5-HT_1A receptors. In a PET study of healthy human volunteers with [¹¹C]WAY100635, higher 5-HT_1A receptor binding was found in women compared to men (Parsey et al., 2002). In addition, Cidis Meltzer et al. (2001) in applying a similar method demonstrated an effect of aging on 5-HT_1A receptor densities in men but not in women. Two single-photon emission computed tomography (SPECT) studies using nonselective radiotracer [¹²³I]β-CIT have shown the effect of sex on 5-HTT and dopamine (DA) transporter availability in the human brain. In the first study, Staley et al. (2001) have reported higher 5-HTT and DA transporter availability in healthy women compared to men. In the second study, lower 5-HTT availability was observed in depressed women compared to depressed men in the diencephalon (Staley et al., 2006). However, to our knowledge, no PET studies have been published so far, of possible differences between the sexes on 5-HTT in healthy subjects.

Possible interaction between 5-HT_1A receptors and 5-HTT has lately been proposed by several pharmacological and genetic studies. It has been shown that treatment with SSRI induces desensitization of 5-HT_1A autoreceptors (Blier and de Montigny, 1998) and that pindolol, a 5-HT_1A receptor antagonist, accelerates the onset of antidepressant effect of SSRIs (Artigas et al., 1996). In human gene-linked polymorphism studies, 5-HTT polymorphisms have been observed to influence 5-HT_1A receptors availability in subjects who are carriers of the short (S) allele of the 5-HTT gene (David et al., 2005, Lee et al., 2005). The findings suggest an interaction of the two biomarkers to be implicated in the regulatory mechanisms of serotonin neurotransmission.

Since both 5-HT_1A receptors and 5-HTT are implicated in psychiatric disorders where the prevalence differs between sexes and several previous studies reported differences in the serotonin system with regard to gender, we undertook the present PET imaging study to examine sex differences in the 5-HT_1A receptor and 5-HTT BP_NDs. We thereby hypothesized that 5-HT_1A receptor and 5-HTT in women and men might serve as an index of susceptibility in the serotonin system. To explore interactions of the two biomarkers contributing sex differences in the regulatory mechanisms of the serotonergic neurotransmission, we studied correlations between 5-HT_1A receptors and 5-HTT binding potential in women and men. Radioligands [¹¹C]WAY100635 and [¹¹C]MADAM were correspondingly used to estimate 5-HT_1A receptor and 5-HTT BP_NDs.