Serotonin 1A Receptor Binding Potential Research Articles

Sex influences the effects of social status on socioemotional behavior and serotonin neurochemistry in rhesus monkeys

BackgroundDespite observed sex differences in the prevalence of stress-related psychiatric conditions, most preclinical and translational studies have only included male subjects. Therefore, it has not been possible to effectively assess how sex interacts with other psychosocial risk factors to impact the etiology and maintenance of stress-related psychopathology. One psychosocial factor that interacts with sex to impact risk for stress-related behavioral and physiological deficits is social dominance. The current study was designed to assess sex differences in the effects of social status on socioemotional behavior and serotonin neurochemistry in socially housed rhesus monkeys. We hypothesized that sex and social status interact to influence socioemotional behaviors as well as serotonin 1A receptor binding potential (5HT1AR-BP) in regions of interest (ROIs) implicated in socioemotional behavior.MethodsBehavioral observations were conducted in gonadally intact adult female (n = 14) and male (n = 13) rhesus monkeys. 5HT1AR-BP was assessed via positron emission tomography using 4-(2ʹ-Methoxyphenyl)-1-[2ʹ-(N-2ʺ-pyridinyl)-p[18F]fluorobenzamido]ethylpiperazine ([18F]MPPF).ResultsAggression emitted was greater in dominant compared to subordinate animals, regardless of sex. Submission emitted was significantly greater in subordinate versus dominant animals and greater in females than males. Affiliative behaviors emitted were not impacted by sex, status, or their interaction. Anxiety-like behavior emitted was significantly greater in females than in males regardless of social status. Hypothalamic 5HT1AR-BP was significantly greater in females than in males, regardless of social status. 5HT1AR-BP in the dentate gyrus of the hippocampus was significantly impacted by a sex by status interaction whereby 5HT1AR-BP in the dentate gyrus was greater in dominant compared to subordinate females but was not different between dominant and subordinate males. There were no effects of sex, status, or their interaction on 5HT1AR-BP in the DRN and in the regions of the PFC studied.ConclusionsThese data have important implications for the treatment of stress-related behavioral health outcomes, as they suggest that sex and social status are important factors to consider in the context of serotonergic drug efficacy.

S.04.08 Serotonin-1A receptor binding potential in dorsal raphe nuclei predicts orbitofrontal reactivity in healthy subjects

S.04.08 Serotonin-1A receptor binding potential in dorsal raphe nuclei predicts orbitofrontal reactivity in healthy subjects

P.1.16 Serotonin-1A receptor binding potential in dorsal raphe nuclei predicts orbitofrontal reactivity in healthy subjects

P.1.16 Serotonin-1A receptor binding potential in dorsal raphe nuclei predicts orbitofrontal reactivity in healthy subjects

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

NeuroImaging bei schizophrenen Erkrankungen

This overview is focused on functional neuroimaging including functional magnetic resonance imaging (fMRI), positron emission tomography (PET) and single photon emission computed tomography (SPECT). Recent evidence for the "dopamine hypothesis of schizophrenia" is summarized including alterations of presynaptic dopamine metabolism and postsynaptic receptor binding potential. Emphasis is given to dopaminergic challenge studies using amphetamine and AMPT. Several PET and SPECT studies have shown a pronounced increase of amphetamine-induced dopamine release as well as decrease of AMPT-induced dopamine depletion in drug-naive schizophrenic patients, indicating a dysregulation of dopaminergic neurotransmission. Results of studies combining amphetamine challenge and the NMDA receptor antagonist ketamine are related to glutaminergic dysfunction and neurotransmitter interactions. FMRI and PET results demonstrating alterations in task-specific functional connectivity between brain areas are discussed with a focus on the prefrontal cortex and temporal structures. Increase of serotonin-1A receptor binding potential in prefrontal and mesotemporal cortex is related to the serotonin-dopamine interaction. Genetic neuroimaging techniques, including voxel-based morphometry (VBM) and fMRI, revealing significant effects of the dopamine metabolizing enzyme COMT on functional activation in prefrontal areas are also discussed. Functional neuroimaging based on challenge-paradigms in PET as well as task-specific state- or trait-dependent alterations of activation patterns in fMRI, seems to be a promising candidate for the development of biological marker tests for schizophrenia.

5-HT1A polymorphism and self-transcendence in mood disorders

Recently, an association between serotonin 1A receptor binding potential and self-transcendence scores at the temperament and character inventory (TCI) has been reported. We tested involvement of 5-HT(1A) gene in this trait, in a sample of 40 remitted mood disorder patients. Subjects with the 5-HT(1A)*C/C genotype showed significantly lower scores at the total self-transcendence and at the sub-scales of transpersonal identification and spiritual acceptance. Our preliminary results further support the involvement of the serotoninergic pattern in the self-transcendence character trait.

Regional Reductions in Serotonin 1A Receptor Binding in Juvenile Myoclonic Epilepsy

Juvenile myoclonic epilepsy (JME) is classified as primarily generalized epilepsy and as such is assumed to lack an anatomic substrate. Although neurochemical abnormalities are probable, few studies have investigated whether they exist in JME. Animal data and the high incidence of myoclonic seizures in serotonin-intoxicated patients suggest that the serotonin system may be disturbed in JME. To test the hypothesis that JME is associated with a disturbed serotonin system and that this disturbance could be reflected in altered serotonin 1A receptor binding. The serotonin 1A receptor binding potential (BP) was measured with positron emission tomography and serotonin 1A receptor antagonist carbonyl-carbon 11-WAY-100635. The BP was calculated using a reference tissue model in several limbic and neocortical regions and the raphe nuclei. Epilepsy clinics of the Karolinska University Hospital, Stockholm, Sweden. Eleven patients with JME and 11 controls were studied. Serotonin 1A receptor BP calculated in a set of volumes of interest. The patients with JME showed a reduced BP in the dorsolateral prefrontal cortex, raphe nuclei, and hippocampus. The observed reductions in serotonin 1A receptor BP suggest that the serotonin system is affected in JME. Although the data give no definitive information about underlying mechanisms, they provide a strong argument for the view that not all brain regions are homogeneously involved in this condition, further questioning the current classification of primarily generalized epilepsy.

Lack of effect of a single dose of hydrocortisone on serotonin 1A receptors in recovered depressed patients measured by positron emission tomography with [ 11C]WAY-100635

Background Elevated cortisol levels might account for the reduction in central serotonin 1A (5-hydroxytryptamine [5-HT] 1A) receptor binding and function observed in patients with major depression. We tested this hypothesis by studying the effect of acute administration of hydrocortisone on 5-HT 1A receptor binding potential (BP) in subjects recovered from depression. Methods We studied 14 subjects (8 male, 6 female) who had recovered from at least two episodes of major depression and had been euthymic and drug free for at least 6 months. Serotonin 1A receptor BP was measured by [ 11C]WAY-100635 in conjunction with positron emission tomography. Subjects were tested on two occasions in a double-blind, random-order, crossover design after administration of either hydrocortisone (100 mg orally) or placebo 12 hours previously. Positron emission tomography scans were analyzed with a region of interest analysis. Results Hydrocortisone treatment did not decrease 5-HT 1A receptor BP either in the hippocampus, which was our a priori hypothesis, or in other cortical 5-HT 1A regions; however, female subjects had a higher 5-HT 1A receptor BP in certain brain areas compared with male subjects. Conclusions These data are consistent with an earlier study in healthy volunteers and do not support the proposal that decreased 5-HT 1A receptor BP in patients with acute major depression is a consequence of cortisol hypersecretion.

Pet imaging of serotonin 1A receptor binding in depression

Background: The serotonin-1A (5HT1A) receptor system has been implicated in the pathophysiology of major depression by postmortem studies of suicide victims and depressed subjects dying of natural causes. This literature is in disagreement, however, regarding the brain regions where 5HT1A receptor binding differs between depressives and controls and the direction of such differences relative to the normal baseline, possibly reflecting the diagnostic heterogeneity inherent within suicide samples. PET imaging using the 5HT1A receptor radioligand, [ 11C]WAY-100635, may clarify the clinical conditions under which 5HT1A receptor binding potential (BP) is abnormal in depression. Methods: Regional 5HT1A receptor BP values were compared between 12 unmedicated depressives with primary, recurrent, familial mood disorders and 8 healthy controls using PET and [ carbonyl- 11C]WAY-100635. Regions-of-interest (ROI) assessed were the mesiotemporal cortex (hippocampus-amygdala) and midbrain raphe, where previous postmortem studies suggested 5HT1A receptor binding is abnormal in depression. Results: The mean 5HT1A receptor BP was reduced 41.5% in the raphe ( p < .02) and 26.8% in the mesiotemporal cortex ( p < .025) in the depressives relative to the controls. Post hoc comparisons showed the abnormal reduction in 5HT1A receptor BP was not limited to these regions, but extended to control ROI in the occipital cortex and postcentral gyrus as well. The magnitude of these abnormalities was most prominent in bipolar depressives ( n = 4) and unipolar depressives with bipolar relatives ( n = 4). Conclusions: Serotonin-1A receptor BP is abnormally decreased in the depressed phase of familial mood disorders in multiple brain regions. Of the regions tested, the magnitude of this reduction was most prominent in the midbrain raphe. Converging evidence from postmortem studies of mood disorders suggests these reductions of 5HT1A receptor BP may be associated with histopathological changes involving the raphe.