5-HT1A Receptor Binding Potential Research Articles

P.1.e.028 Resting -state functional connectivity of the raphe nuclei

Positron emission tomography (PET) and [11C]WAY-100635 were used to examine the effect of age on serotonin-1A (5-HT1A) receptor binding potential (BP) in 19 healthy subjects. Regions of interest (ROI) were drawn on the co-registered magnetic resonance imaging (MRI) in orbitofrontal (OFC), dorsolateral prefrontal (DLPFC), anterior cingulate (ACC), lateral (LTC), and mediotemporal (MTC), parietal, occipital and cerebellar cortex, and the raphe nuclei. BP values were calculated using a simplified reference tissue method. In addition, a voxelwise analysis was performed using SPM99. Voxelwise analysis revealed a significant global decrease of 5-HT1A BP with age (set level < .001). ROI analysis revealed significant age-related 5-HT1A BP decreases in DLPFC (r = −0.56), ACC (r = −0.44), OFC (r = −0.42), LTC (r = −0.40), parietal (r = −0.65), and occipital cortex (r = −0.43), but not in MTC or raphe nuclei. Overall, cortical 5-HT1A BP declined by approximately 10% per decade, except for the MTC, where we did not find a significant age effect. Hence, careful age matching may be recommended for future studies using PET and [11C]WAY-100635 to examine 5-HT1A receptors.

P02-337 - Cortisol plasma levels are associated with serotonin - 1A receptor binding in postmenopausal women

IntroductionAlterations of the serotonin-1A receptor (5-HT1A) and the hypothalamic-pituitary-adrenal (HPA) axis have been reported in depression and anxiety disorders. We previously showed a strong negative correlation between cortisol plasma levels and 5-HT1A receptor binding potential (BP) in patients with social anxiety disorder but not in healthy controls using PET [1].ObjectivesTo investigate the relationship of cortisol and the 5-HT1A BP in postmenopausal women, a population that is at increased risk of suffering from depressive symptoms.MethodsSubjects: 19 postmenopausal women, aged 55.26 ± 4.98, medication free, no current substance abuse or hormone replacement therapy.PETDynamic measurements (50 frames, 90 min) were performed using the radioligand [carbonyl-11C]WAY100635 and a GE-Advance scanner. PET data were normalized to a ligand-specific template [2]. Regions-of-interest (ROI) were defined as given in [3]. TACs within ROIs were averaged and the 5-HT1A receptor BP was quantified using Logan-plot and PMOD 3.1. Measurement of total cortisol plasma levels was done using electrochemoluminescence.ResultsWe found negative correlations between cortisol and 5-HT1A BP in the midbrain (Spearman's rs = −0.54, p = 0.02), the median raphe nucleus (rs = −0.47, p = 0.04) and the nucleus accumbens (rs = −0.505, p = 0.03).ConclusionsIn line with our previous findings [1], the observed negative association between cortisol plasma levels and 5-HT1A BP might reflect an increased vulnerability for mood disorders in postmenopausal women.

Chronic stress is linked to 5-HT1A receptor changes and functional disintegration of the limbic networks

There are increasing reports about stress related cognitive and psychic declines in subjects who have no psychiatric premorbidity, depression, or major life trauma. Yet, little is known about the underlying neurobiology. Based on the typical symptomatology, fMRI data suggesting that stress activates the limbic circuits, and animal data showing a major involvement of the 5-HT1A receptor in stress regulation, we hypothesized that enduring daily stress causes widespread limbic dysfunctions, and specific changes of the 5-HT1A receptor.To test these hypotheses combined PET studies were carried out in 16 chronically stressed, and 16 non-stressed subjects. Limbic function was tested by measuring cerebral blood flow during rest, and when using an odor activation paradigm. 5-HT1A receptor binding potential (BP) was assessed with [11C]WAY100635. All subjects went through a battery of neuropsychological tests.Stressed subjects showed a functional disconnection between the amygdala and ACC/medial prefrontal cortex (mPFC), and an impaired odor activation of the ACC. They also displayed a reduced 5-HT1A receptor BP in the anterior cingulate (ACC), the insular-cortex, and the hippocampus. Their performance in attention-, odor discrimination-, and semantic memory tasks was impaired, and correlated with the BP-values in the respective region. The degree of reported stress was inversely correlated with activation of ACC, and the 5-HT1A receptor BP in the amygdala and hippocampus.Enduring every day psychosocial stress seems to be associated with a limbic reduction of 5-HT1A receptor binding and functional disintegration of ACC/mPFC. These changes support the notion of an impaired top-down regulation of stress stimuli, and identify potential targets for early treatment.

Escitalopram Enhances the Association of Serotonin-1A Autoreceptors to Heteroreceptors in Anxiety Disorders

Selective serotonin reuptake inhibitors (SSRIs) represent one of the most common treatment options in major depression and anxiety disorders. By blocking the serotonin transporter, SSRIs modulate serotonergic neurotransmission as well as the function of autoreceptors and heteroreceptors. However, treatment-induced changes on a network level primarily remain unknown. Thus, we evaluated the association between serotonin-1A (5-HT1A) autoreceptors and heteroreceptors before and after SSRIs. Twenty-one patients with anxiety disorders underwent positron emission tomography using [carbonyl-11C]WAY-100635 before and after 12 weeks of escitalopram treatment; 15 of them completed the study protocol. Additionally, 36 drug-naive healthy controls were measured once. The 5-HT1A receptor binding potential (BPND) was quantified for the dorsal raphe nucleus (DRN) using a region-of-interest approach and for the entire brain by calculating parametric maps. Voxel-wise linear regression was applied between DRN autoreceptor and whole-brain heteroreceptor 5-HT1A BPND. Consistent with previous observations, healthy subjects showed widespread positive correlations of 5-HT1A BPND between autoreceptors and heteroreceptors. Comparing patients before versus after escitalopram treatment revealed enhanced associations of autoreceptor-to-heteroreceptor 5-HT1A BPND within the amygdala and hippocampus (R2=0.21-0.28 vs 0.49-0.81; p<0.05-0.001). In contrast, no significant SSRI-induced changes were found for correlations of heteroreceptor-to-heteroreceptor 5-HT1A BPND between several limbic regions. This interregional approach suggests a treatment-induced reinforcement of the association of 5-HT1A binding between autoreceptors and heteroreceptors specifically in areas involved in anxiety disorders. These findings provide complementary information about treatment effects on a network level and confirm the central role of the DRN as a prime regulatory area.

Lateralization of the serotonin-1A receptor distribution in language areas revealed by PET

Lateralization is a well described aspect of the human brain. A plethora of morphological, cytological and functional studies describes hemispheric asymmetry in auditory and language areas. However, no study has reported cortical lateralization in the healthy human brain in vivo on the level of neurotransmitter receptors and in relation to functional organization so far. In this study, we assessed the distribution of the main inhibitory serotonergic receptor (the 5-HT1A receptor) and analyzed its regional binding with regard to hemisphere, sex and plasma levels of sex steroid hormones (testosterone, estradiol, progesterone). We quantified the 5-HT1A receptor binding potential by positron emission tomography (PET) using the highly selective and specific radioligand [carbonyl-11C]WAY-100635 and measured hormone levels in thirty-four (16 females, 18 males) healthy right-handed subjects. The obtained data were analyzed in an automated region of interest (ROI) based approach investigating 14 auditory, language and limbic areas. We found significantly higher 5-HT1A receptor binding in the superior and middle frontal gyri of the right hemisphere, the triangular and orbital parts of the inferior frontal gyrus, the supramarginal gyrus, the superior gyrus of the temporal pole and the middle temporal gyrus. Regions of the primary and secondary auditory cortex (Heschl's gyrus and superior temporal gyrus) and the Rolandic operculum displayed significantly higher receptor binding in the left hemisphere. 5-HT1A receptor binding was 1.8–2.9% higher in right frontal ROIs and 2–3.6% higher in left primary and secondary auditory regions. There was no hemispheric difference in 5-HT1A receptor binding in the hippocampus, amygdala, and insula. Post-hoc testing suggested that lateralization of 5-HT1A receptor binding differed between the sexes in the triangular part of the inferior frontal gyrus. For the first time, this PET study shows lateralization of the main inhibitory receptor of the serotonergic system in functionally asymmetric organized regions of the healthy human brain in vivo.

Interictal Brain 5-HT1A Receptors Binding in Migraine Without Aura: A 18F-MPPF-PET Study

In this study we aimed to assess the brain distribution of 5-HT(1A) receptors in migraine patients without aura. Ten female migraine patients and 24 female healthy volunteers underwent magnetic resonance imaging and positron emission tomography using a radioligand antagonist of 5-HT(1A) receptors [4-(2'-methoxyphenyl)-1-[2'-(N-2-pirydynyl)-p-fluorobenzamido]-ethylpiperazine ((18)F-MPPF)]. A simplified reference tissue model was used to generate parametric images of 5-HT(1A) receptor binding potential (BP) values. Statistical Parametrical Mapping (SPM) analysis showed increased MPPF BP in posterior cortical areas and hippocampi bilaterally in patients compared with controls. Region of interest (ROI) analysis showed a non-significant trend in favour of a BP increase patients in cortical regions identified by the SPM analysis except in hippocampi, left parietal areas and raphe nuclei. During the interictal period of migraine patients without aura, the increase of MPPF BP in posterior cortical and limbic areas could reflect an increase in receptor density or a decrease of endogenous serotonin, which could explain their altered cortical excitability.

The molecular background of sex difference in depressive disorders: still an enigma

There is no doubt that adult females are significantly more often affected by depression and anxiety disorders than males. Virtual every study enrolls more women than men and it is assumed that the number of women suffering from depression doubles that of men. Interestingly, this difference is not present before adolescence. Not only the incidence and prevalence of depression is gender-specific, the same is true for the clinical phenomenology. The female excess is more pronounced in comorbid depression and anxiety and less in the pure forms. Other forms affecting women to a significantly higher degree than other subtypes are the so-called atypical depression [1] and somatic depression [2]. The main pathophysiological concept of depression relies on the biogenic amine 5-hydroxytryptophan (5HT) named serotonin. There is convincing evidence that the central serotonergic system plays a key role in the development, treatment and response rate of this affective disorder. Serotonin depletion induces depression in vulnerable subjects. Pharmacological restoration of high extracellular serotonin level relieves symptoms and is associated with termination of depressive episodes, which are frequently observed in the Western population and represent a relevant socioeconomic and medical problem. So far, the unequivocal facts for which strong evidence exist from epidemiologic studies and animal experiments. For in vivo studies on brain function in depression and other psychiatric disorders, nuclear medicine imaging provides a valuable and powerful imaging tool. By positron emission tomography, the serotonin transporter, the serotonin 2A and the serotonin 1A receptor binding potential (BP) can be selectively quantified. In this regard, particular interest is put on PET with [carbonyl-C]WAY-100635, a highly selective ligand for the 5-HT1A receptor that is the main inhibitory serotonergic receptor subtype. One should expect that, based on the overwhelming evidence for the predominance of female depressive patients, this armamentarium can easily visualise the molecular sex differences in the serotonergic system. However, the results remain inconsistent despite that the majority of investigators demonstrated a reduction of 5-HT1A receptor BP in distinct brain regions of depressive subjects [3–5], whereas no significant 5-HT1A receptor BP difference was found in patients with major depressive disorder (MDD) in comparison to controls in another comparable study by Parsey et al. [6]. Given that females show a significant predominance in depression, the consideration of a sex difference in 5-HT1A receptor BP is quite compelling. Indeed, a very recent study demonstrated a higher 5-HT1Areceptor BP and a lower serotonin transporter BP in females compared to males in healthy subjects [7]. Some years earlier, Parsey et al. also demonstrated a higher 5-HT1A receptor BP in females in several brain regions playing a role in mood disorders [8]. The study of Stein et al. in this EJNMMI issue focused on the 5-HT1A receptor BP in a sample of young healthy volunteers, determining the structure by two independent methods with the surprising result that there was a trend to though nonsignificant lower 5-HT1A receptor BP in females than in males [9]. These results were obtained by both an automated template-based method and by visual region of Eur J Nucl Med Mol Imaging (2008) 35:2156–2158 DOI 10.1007/s00259-008-0928-5

Correlation between serotonin synthesis and 5-HT1A receptor binding in the living human brain: A combined α-[11C]MT and [18F]MPPF positron emission tomography study

Serotonin (5-HT) is one of the major neurotransmitters and has been implicated in a wide variety of cerebral functions. Several lines of evidence indicate that 5HT1A receptors exert a negative feedback in the synthesis and release of serotonin. While most of what is known about serotonin comes from studies in animals, much less empirical evidence exists about the serotonergic system in the living human brain. This study aims to assess the correlation between serotonin synthesis and 5-HT1A receptor binding using positron emission tomography (PET) in humans. Six healthy male volunteers underwent 2 PET scans in the same day: one measuring α-[11C]MT K⁎ [ml/g/min] trapping constant (a measure of serotonin synthesis) and one measuring 5-HT1A receptor binding potential BPND with [18F]MPPF. Volumes of interest (VOIs) selected a priori included: anterior cingulate cortex (ACC), anterior insula, hippocampus, amygdala, thalamus, hypothalamus and midbrain raphe nuclei. Correlation analyses were conducted voxel-by-voxel and with manually traced VOIs. A significant negative correlation between serotonin synthesis and 5-HT1A binding potential was found bilaterally in hippocampus and anterior insula and in the left ACC. The combination of [18F]MPPF and α-[11C]MT PET offers a means to investigate key determinants of 5-HT neurotransmission under physiological and psychopathological conditions in the human brain in vivo.

Multimodal imaging of human early visual cortex by combining functional and molecular measurements with fMRI and PET

Receptor distribution patterns of neurotransmitters and distinct functional fields of the human brain appear to be tightly connected with respect to their topological allocation along the cerebral cortex. There is, however, considerable lack of human data directly demonstrating this association in vivo. Here, we assessed the relationship between the distribution of the major inhibitory serotonergic neurotransmitter receptor, the 5-HT1A subtype, and the functional organization within early visual cortex defined by retinotopic mapping. The 5-HT1A receptor-binding potential was quantified by positron emission tomography (PET) using the highly selective and specific radioligand [carbonyl-11C]WAY-100635 in seven healthy subjects. The retinotopic maps and borders determined by functional magnetic resonance imaging (fMRI) were compared to the receptor distribution employing surface-based region of interest analysis in each of these subjects. We found a significant difference in receptor-binding potential in the functionally defined primary (V1) compared to secondary (V2) visual area, as V1 exhibits only 68% of receptor binding found in V2 in both hemispheres, which is consistent with postmortem data. Our in vivo findings clearly support prior assumptions of a link between receptor distribution and functional fields of the human cortex.

P.3.23 Molecular imaging of early visual cortex by combining pet and fMRI

Animal models revealed that the serotonin-1A (5-HT1A) receptor modulates gray matter structure. However, there is a lack of evidence showing the relationship between 5-HT1A receptor concentration and gray matter in the human brain in vivo. Here, to demonstrate an association between the 5-HT1A receptor binding potential, an index for receptor concentration, and the local gray matter volume (GMV), an index for gray matter structure, we measured 35 healthy subjects with both positron emission tomography (PET) and structural magnetic resonance imaging (MRI). We found that regional heteroreceptor binding was positively associated with GMV in distinctive brain regions such as the hippocampi and the temporal cortices in both hemispheres (R2 values ranged from 0.308 to 0.503, p < 0.05 cluster-level FDR-corrected). Furthermore, autoreceptor binding in the midbrain raphe region was positively associated with GMV in forebrain projection sites (R2 = 0.656, p = 0.001). We also observed a broad range between 5-HT1A receptor binding and GMV. Given the congruence of altered 5-HT1A receptor concentrations and GMV reduction in depression or Alzheimer's disease as reported by numerous studies, these results might provide new insights towards understanding the mechanisms behind GMV alterations observed in these brain disorders.

Serotonin 1A receptor reductions in postpartum depression: a positron emission tomography study

To measure brain serotonin-1A (5HT1A) receptor binding potential (BP) in healthy and depressed postpartum women. 5HT1A receptor BP was measured with positron emission tomography by using [(11)C]WAY100635 a single time. Multivariate analysis of variance was used to determine depression effects on 5HT1A receptor BP in relevant brain regions. An academic research environment. Seven postpartum healthy controls and nine postpartum depressed (PD) subjects with perinatal (antepartum or postpartum) depression onset. Of the nine PD subjects, five had unipolar depression, and four had bipolar disorder. None. 5HT1A receptor BP. Age, time since delivery, and reproductive hormones did not differ between groups. Postsynaptic 5HT1A receptor binding in postpartum depression was reduced 20%-28% relative to controls, with most significant reductions in anterior cingulate and mesiotemporal cortices. Postsynaptic 5HT1A receptor binding is reduced in PD women by a similar magnitude as has been shown in other depression samples. The postpartum hormonal milieu and the large proportion of bipolar spectrum subjects in the PD group may have accentuated this finding in this small sample. Recognition of this neurobiological deficit in postpartum depression may be useful in the development of treatments and prevention strategies for this disabling disorder.

P.1.06 Gender differences in hypothalamic serotonin-1A receptor distribution revealed by PET

We performed positron emission tomography using [carbonyl-11C]WAY-100635, a serotonin 1A (5-HT1A) receptor antagonist, in 13 patients with temporal lobe epilepsy (TLE) and in 13 controls. 5-HT1A receptor distribution mapping allowed correct lateralization of the epileptogenic temporal lobe in all patients. 5-HT1A receptor binding potential (BPND) was significantly reduced in almost all temporal regions of the epileptogenic lobe. Compared with controls, the patients had significantly decreased BPND values in the hippocampus, parahippocampal gyrus, and amygdala. The asymmetry index (AI), which characterizes the interhemispheric asymmetry in BPND, was significantly higher in patients than in controls in most regions. Depression scores were not significantly correlated with BPND or AI values. Our data provide further evidence of functional changes in the serotonergic system in TLE. Molecular imaging of the 5-HT1A receptor may help to define the in vivo neurochemistry of TLE, and may provide a valuable tool in the noninvasive presurgical assessment of patients with medically refractory TLE.

Reduced Serotonin-1A Receptor Binding in Social Anxiety Disorder

Results from studies in serotonin-1A (5-HT1A) knockout mice and previous positron emission tomography (PET) studies in humans imply a role for 5-HT1A receptors in normal state anxiety as well as in certain anxiety disorders. The objective of this study was to investigate 5-HT1A receptor binding potential (BP) in social anxiety disorder (SAD). Using PET and [carbonyl-11C]WAY-100635, we compared a homogeneous group of 12 unmedicated, male SAD patients with 18 healthy control subjects (HC). A multivariate ANOVA with all regional BP values as dependent variables, age and four radiochemical variables as covariates was performed. We found a significantly lower 5-HT1A BP in several limbic and paralimbic areas but not in the hippocampus (p = .234) of SAD patients. The difference in 5-HT1A binding was most significant in the amygdala (-21.4%; p = .003). There was also a more than 20% lower 5-HT(1A) BP of SAD patients in the anterior cingulate cortex (p = .004), insula (p = .003), and dorsal raphe nuclei (p = .030). The lower 5-HT1A binding in the amygdala and mesiofrontal areas of SAD patients is consistent with 1) preclinical findings of elevated anxiety in 5-HT1A knockout mice, 2) a previous PET study in healthy volunteers showing an inverse correlation between 5-HT1A BP and state anxiety, and 3) another human PET study in patients with panic disorder showing reduced 5-HT1A binding, thus corroborating the potential validity of 5-HT1A receptors as targets in the treatment of human anxiety disorders.

Search for correlations between serotonin 5-HT1A receptor expression and cognitive functions—a strategy in translational psychopharmacology

Animal studies and studies of human aging have suggested that the serotonin 5-HT1A receptor may serve as a biomarker for cognitive functioning and a target for pharmacological treatment of cognitive deficits. The purpose of this positron emission tomography (PET) study was to search for relationships between interindividual variability in serotonin 5-HT1A receptor binding potential (BP) and cognitive functioning. Twenty-four male control subjects, age 20-55 years, were examined with [11C]WAY100635 PET and a battery of cognitive tests. 5-HT1A receptor binding potential were calculated for the raphe nuclei, the hippocampus and the neocortex. Correlation coefficients between BP and cognitive performance were obtained for each region. There was a severalfold of variability in 5-HT1A BP between individuals. We found no significant correlation between regional [11C]WAY100635 binding and cognitive performance. The results do not provide support for involvement of the 5-HT1A receptor in cognitive functioning in man and question the predictive validity of some currently used animal models in translational neuroscience.

Use of an [18F]setoperone bolus + infusion protocol to delineate age related reduction in 5HT2A receptor binding potential in female rhesus monkeys

The physiologic process of aging is known to have an effect on the brain concentration of some monoaminergic receptors. In addition, studies have suggested a causal link between sex hormones and these receptor changes. Accordingly, we were interested to see in our colony of geriatric rhesus monkeys if we could demonstrate an age- and sex-related difference in 5HT2A receptor concentration in the brain using the PET tracer [18F] Setoperone. This tracer has a 10-50x greater affinity for the 5-HT2A receptor than the D2 receptor, but provides a specific signal for both receptors in vivo. Since D2 receptor density is low in cortical regions and 5HT2A is high, while the opposite is true in striatum, [18F] Setoperone can be used to evaluate both receptors. Chase studies with risperidone, a non-selective antagonist of both 5-HT2A and D2 demonstrated significant displacement of the tracer from both 5-HT2A and D2 receptors. Studies were conducted in propofol anesthetized, older (n=5, 26–29 yrs) female Rhesus monkeys and young female (n=2, 8 yrs) and male Rhesus monkeys (n=2, 8 and 10 yrs) as controls in an ECAT HR+ PET camera. At the time of the scans, estradiol levels were 95 11 pg/ml in the young female monkeys compared to 35.3 6.5 pg/ml in the older monkeys. [18F] Setoperone was administered as a bolus followed by a matched constant-rate infusion for 200 minutes, adjusted to compensate for tracer elimination in the bolus, to achieve steady-state brain uptake. Tracer uptake reached a steady state in the brain after 120 min (reflected by constant target-to-cerebellum ratio). Indices of 5HT2A and D2 receptor binding were calculated from the occipital cortex/cerebellum and striatum/cerebellum ratios between 140 and 200 minutes, respectively. The cerebellum was used as a reference region since it is essentially devoid of both 5-HT2A and D2 receptors. The uptake ratios of occipital cortex/cerebellum binding (an index of the 5-HT2A receptor binding potential) and striatum/cerebellum (an index of the D2 receptor binding potential) were calculated. The test-retest reproducibility of this protocol was found to be < 10% in male Rhesus monkeys. Results indicated an 15% and 24% reduction in binding potential for D2 and 5HT2A receptors respectively in the older females compared to the young females. As expected, the binding potential for 5HT2A receptor in young males was comparable to that in the young females. These studies suggest [18F] Setoperone may be used in a convenient protocol to show age related reductions in 5HT2A and D2 receptor binding in post-menopausal woman. An advantage of using such a protocol with [18F] setoperone is that both 5-HT2A and D2 receptors can be evaluated in the same study.

A Functional Genetic Variation of the Serotonin (5-HT) Transporter Affects 5-HT1AReceptor Binding in Humans

In humans, 5-HT1A receptors are implicated in anxiety and depressive disorders and their treatment. However, the physiological and genetic factors controlling 5-HT1A receptor expression are undetermined in health and disease. In this study, the influence of two genetic factors on 5-HT1A receptor expression in the living human brain was assessed using the 5-HT1A-selective positron emission tomography (PET) ligand [11C]WAY 100635. After the genotyping of 140 healthy volunteers to study population frequencies of known single nucleotide polymorphisms (SNPs) in the 5-HT1A receptor gene, the influence of the common SNP [(-1018) C>G] on 5-HT1A receptor expression was examined in a group of 35 healthy individuals scanned with [11C]WAY 100635. In the PET group, we also studied the influence of a common variable number tandem repeat polymorphism [short (S) and long (L) alleles] of the 5-HT transporter (5-HTT) gene on 5-HT1A receptor density. Whereas, the 5-HT1A receptor genotype did not show any significant effects on [11C]WAY 100635 binding, 5-HT1A receptor binding potential values were lower in all brain regions in subjects with 5-HTTLPR short (SS or SL) genotypes than those with long (LL) genotypes. Although the PET groups are necessarily a small sample size for a genetic association study, our results demonstrate for the first time that a functional polymorphism in the 5-HTT gene, but not the 5-HT1A receptor gene, affects 5-HT1A receptor availability in man. The results may offer a plausible physiological mechanism underlying the association between 5-HTTLPR genotype, behavioral traits, and mood states.

Brain 5-HT 1A receptor binding in chronic fatigue syndrome measured using positron emission tomography and [ 11C]WAY-100635

Research from neuroendocrine challenge and other indirect studies has suggested increased central 5-HT function in chronic fatigue syndrome (CFS) and increased 5-HT1A receptor sensitivity. We assessed brain 5-HT1A receptor binding potential directly using the specific radioligand [11C]WAY-100635 and positron emission tomography (PET). We selected 10 patients from a tertiary referral clinic who fulfilled the CDC consensus criteria for CFS. To assemble a homogenous group and avoid confounding effects, we enrolled only subjects who were completely medication-free and did not have current comorbid psychiatric illness. We also scanned 10 healthy control subjects. There was a widespread reduction in 5-HT1A receptor binding potential in CFS relative to control subjects. This was particularly marked in the hippocampus bilaterally, where a 23% reduction was observed. There is evidence of decreased 5-HT1A receptor number or affinity in CFS. This may be a primary feature of CFS, related to the underlying pathophysiology, or a finding secondary to other processes, such as previous depression, other biological changes or the behavioral consequences of CFS.

Estradiol Effects on the Postmenopausal Brain

Back to table of contents Previous article Next article Letter to the EditorFull AccessEstradiol Effects on the Postmenopausal BrainEYDIE L. MOSES-KOLKO, M.D., CAROLYN CIDIS MELTZER, M.D., PHIL GREER, M.S., MERYL BUTTERS, Ph.D., SARAH L. BERGA, M.D., GWENN SMITH, Ph.D., and WAYNE C. DREVETS, M.D., EYDIE L. MOSES-KOLKOSearch for more papers by this author, M.D., CAROLYN CIDIS MELTZERSearch for more papers by this author, M.D., PHIL GREERSearch for more papers by this author, M.S., MERYL BUTTERSSearch for more papers by this author, Ph.D., SARAH L. BERGASearch for more papers by this author, M.D., GWENN SMITHSearch for more papers by this author, Ph.D., and WAYNE C. DREVETSSearch for more papers by this author, M.D., Pittsburgh, Pa.Published Online:1 Nov 2004https://doi.org/10.1176/appi.ajp.161.11.2136AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: We commend Akira Kugaya, M.D., Ph.D., and colleagues (1) on their brief report on serotonin 2A (5-HT2A) receptors in postmenopausal women. Characterization of the effects of gonadal steroids on neuroreceptor pharmacology and cognitive function holds great importance to clinical care and cognitive neuroscience research. Consistent with the article by Dr. Kugaya et al., we previously reported that 5-HT2A receptor binding potential significantly increased in postmenopausal women during administration of transdermal estradiol, 0.1 mg/day for 8 to 14 weeks, followed by combined transdermal estradiol and progesterone, 100 mg b.i.d. (2 to 6 weeks), with positron emission tomography and the selective 5-HT2A receptor radioligand [18F]altanserin. Dr. Kugaya et al. correctly cited this publication as reporting a “subthreshold” effect of estradiol alone on increasing 5-HT2A receptor binding potential in specific brain regions of interest. However, we alert readers to our more recent publication (2), in which our original image data were analyzed voxel by voxel using statistical parametric mapping, a technique similar to that applied by Dr. Kugaya et al. Consistent with the work of Dr. Kugaya et al., this approach showed that administration of estradiol alone increased 5-HT2A receptor binding potential in multiple brain regions that had not been examined in our initial region-of-interest analysis (3), which included the right superior frontal gyrus, the right ventrolateral prefrontal cortex, the left inferior parietal cortex, and the left temporal polar cortex. Furthermore, in a post hoc analysis that employed a lower significance threshold for identifying voxels with increased 5-HT2A receptor binding potential after estradiol treatment (the same threshold used by Dr. Kugaya et al.), we observed widespread increases in estradiol-related cortical 5-HT2A receptor binding potential.Given the clinical risks and benefits associated with the hormone replacement therapy regimens investigated in recent large-scale clinical trials (4, 5), mechanistic studies such as these may help shift the focus to alternate hormone replacement therapy regimens that may exert potentially beneficial effects on brain function. Both our study and that of Dr. Kugaya et al. lack the sensitivity needed to establish relationships between changes in 5-HT2A receptor binding and cognitive function or emotional behavior, which minimizes the potential for making clinical inferences. The sensitivity of both studies was limited by small group sizes and ceiling/floor effects on neuropsychological test performance in cognitively intact euthymic women. The findings of these studies nevertheless support the initiation and inform the design of future studies aimed at investigating neurobiological bases for the potential neuropsychiatric benefits of such treatments in specific patient populations.

Widespread increases of cortical serotonin type 2A receptor availability after hormone therapy in euthymic postmenopausal women

Objective To use statistical parametric mapping to determine the extent of previously reported serotonin type 2A (5HT 2A) receptor binding potential (BP) increases in postmenopausal women following hormone therapy. Design Repeated measures positron emission tomography (PET) study. Setting Academic research environment. Patient(s) Five healthy, postmenopausal women. Intervention(s) Serial PET images of [ 18F]altanserin uptake were acquired to measure 5HT 2A receptor BP at menopausal baseline, following estradiol (E 2), and following combined E 2 + micronized progesterone (P 4). Main outcome measure(s) 5HT 2A receptor BP. Result(s) Combined E 2 + P 4 treatment was associated with significant increases in the 5HT 2A receptor BP increases in widespread areas of cerebral cortex. Treatment with E 2 alone was also associated with widespread cortical BP increases, although these changes reached statistical significance in fewer regions. The rate of [ 18F]altanserin metabolism was significantly decreased in the E 2 + P 4 condition relative to menopausal baseline, but this difference did not appear to correlate with changes in 5HT 2A receptor BP. Conclusion(s) Estradiol priming followed by combined E 2 + P 4 is associated with widespread increases in 5HT 2A receptor BP in the cerebral cortex, consistent with the E 2-associated increases in 5HT 2A receptor density previously observed in experimental animals.

Serotonin 5-HT1A receptor binding potential declines with age as measured by [11C]WAY-100635 and PET.

Positron emission tomography (PET) and [11C]WAY-100635 were used to examine the effect of age on serotonin-1A (5-HT1A) receptor binding potential (BP) in 19 healthy subjects. Regions of interest (ROI) were drawn on the co-registered magnetic resonance imaging (MRI) in orbitofrontal (OFC), dorsolateral prefrontal (DLPFC), anterior cingulate (ACC), lateral (LTC), and mediotemporal (MTC), parietal, occipital and cerebellar cortex, and the raphe nuclei. BP values were calculated using a simplified reference tissue method. In addition, a voxelwise analysis was performed using SPM99. Voxelwise analysis revealed a significant global decrease of 5-HT(1A) BP with age (set level <.001). ROI analysis revealed significant age-related 5-HT(1A) BP decreases in DLPFC (r = -0.56), ACC (r = -0.44), OFC (r = -0.42), LTC (r = -0.40), parietal (r = -0.65), and occipital cortex (r = -0.43), but not in MTC or raphe nuclei. Overall, cortical 5-HT(1A) BP declined by approximately 10% per decade, except for the MTC, where we did not find a significant age effect. Hence, careful age matching may be recommended for future studies using PET and [11C]WAY-100635 to examine 5-HT1A receptors.