Association between corticotropin-releasing hormone receptor 2 (CRHR2) gene polymorphism and personality traits

Corticotropin-releasing hormone (CRH) has been implicated in the pathophysiology of anxiety disorders and depression. Corticotropin-releasing hormone receptor 2 (CRHR2) is one of the receptors that mediate CRH signal. The purpose of the present study was to investigate the association between the CRHR2 gene and personality traits, evaluated using the Revised NEO Personality Inventory (NEO PI-R), in 243 healthy Japanese subjects. As a result, significant association was observed between the polymorphism in intron 2 (rs2267717) and Openness (P = 0.004, uncorrected, anova), while no relationship was observed concerning Neuroticism. The present result suggests an association between CRHR2 and the personality trait of Openness.     

The association between bodily anxiety symptom dimensions and the scales of the Revised NEO Personality Inventory and the Temperament and Character Inventory

The association between anxiety disorders and different measures of personality has been extensively studied to further the understanding of etiology, course, and treatment, and to possibly prevent the development of anxiety disorders. We have proposed a hierarchical model of bodily anxiety symptoms with 1 second-order severity factor and 5 first-order factors: cardio-respiratory, gastro-intestinal, autonomic, vertigo, and tension. The aim of this study was to investigate whether personality traits were differentially related to distinct symptom subdimensions or exclusively related to the general severity factor. Structural equation modeling of data on 120 patients with a primary diagnosis of social phobia and 207 patients with a primary diagnosis of panic disorder was used to examine the association between anxiety symptom dimensions and the scales of the Temperament and Character Inventory and of the Revised NEO Personality Inventory. When both sets of personality measures were simultaneously modeled as predictors, the Revised NEO Personality Inventory scales, neuroticism and extraversion, remained significantly associated with the severity factor, whereas the association between the Temperament and Character Inventory dimensions, harm avoidance and novelty seeking, and the severity factor became nonsignificant. Harm avoidance was negatively associated with the vertigo first-order factor, whereas neuroticism was negatively associated with the cardio-respiratory first-order factor, indicating that personality factors may be differentially related to specific anxiety subdimensions.     

Increased 5-HT(2A) receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [(11)C]MDL 100,907

OBJECTIVE: A previous positron emission tomography (PET) study reported increased serotonin 5-HT(2A) receptor binding in unmedicated depressed patients with high scores on the Dysfunctional Attitudes Scale. The purpose of the present study was to use the highly selective 5-HT(2A) receptor ligand [(11)C]MDL 100,907 in a PET imaging paradigm to assess 1) 5-HT(2A) receptor binding potential in euthymic subjects with a history of recurrent depression and 2) the relationship between receptor binding and scores on the Dysfunctional Attitudes Scale. METHOD: Cortical 5-HT(2A) receptor binding was measured in 20 unmedicated, fully recovered unipolar depressed patients and 20 age- and gender-matched comparison subjects. Regional estimates of binding potential were obtained using a reversible plasma input function compartmental model and the cerebellum as a reference region to estimate the free and non-specifically bound [(11)C]MDL 100,907 in brain tissue. RESULTS: Relative to the comparison subjects, the recovered depressed patients demonstrated significantly higher 5-HT(2A) receptor binding potential in the frontal cortex (mean increase: 19%), parietal cortex (mean increase: 25%), and occipital cortex (mean increase: 19%). 5-HT(2A) receptor binding potential correlated negatively with age in both patients and comparison subjects and positively with the Dysfunctional Attitudes Scale in the recovered patients. CONCLUSIONS: These findings should be considered preliminary but suggest that recovered subjects with a history of recurrent major depression have elevated binding potential of cortical 5-HT(2A) receptors. The correlation of increased 5-HT(2A) receptor binding potential with increased scores on Dysfunctional Attitudes Scale supports earlier work suggesting that increased 5-HT(2A) receptor availability characterizes a group of depressed patients with high levels of dysfunctional attitudes.     

Dopamine D4 receptor gene polymorphism and personality traits in healthy volunteers

An association between long alleles of a variable number tandem repeat (VNTR) polymorphism in the dopamine receptor D4 gene and the extraversion related personality traits Excitement and Novelty Seeking has been reported in healthy subjects. In an attempt to replicate the previous findings, 256 healthy Caucasian volunteers were analysed for a potential relationship between the dopamine receptor D4 exon III VNTR polymorphism and Extraversion as assessed by the Revised Neo Personality Inventory (NEO PI-R). The present study did not yield evidence for an association between Extraversion and the dopamine receptor D4 polymorphism. Received: 8 June 1999 / Accepted: 4 April 2000     

No association between the Clara cell secretory protein (CC16) gene polymorphism and personality traits

Clara cell secretory protein (CC16) is an anti-inflammatory protein expressed in the respiratory tract. Several studies have suggested the association between CC16 and mental disturbances, such as schizophrenia, depression, and post-traumatic stress disorder. In the present study, we investigated the association between the CC16 gene A38G polymorphism and personality traits in 214 healthy Japanese subjects. Personality traits were evaluated by using the Revised NEO Personality Inventory (NEO PI-R) and the State-Trait Anxiety Inventory (STAI). As a result, no significant association was observed between the genotypes and the scores of the NEO PI-R or the STAI. The present results suggest that CC16 may not have a major role in the development of personality traits.     

The serotonin system and spiritual experiences

OBJECTIVE: The serotonin system has long been of interest in biological models of human personality. The purpose of this positron emission tomography (PET) study was to search for relationships between serotonin 5-HT(1A) receptor density and personality traits. METHOD: Fifteen normal male subjects, ages 20-45 years, were examined with PET and the radioligand [(11)C]WAY100635. Personality traits were assessed with the Swedish version of the Temperament and Character Inventory self-report questionnaire. Binding potential, an index for the density of available 5-HT(1A) receptors, was calculated for the dorsal raphe nuclei, the hippocampal formation, and the neocortex. For each region, correlation coefficients between 5-HT(1A) receptor binding potential and Temperament and Character Inventory personality dimensions were calculated and analyzed in two-tailed tests for significance. RESULTS: The authors found that the binding potential correlated inversely with scores for self-transcendence, a personality trait covering religious behavior and attitudes. No correlations were found for any of the other six Temperament and Character Inventory dimensions. The self-transcendence dimension consists of three distinct subscales, and further analysis showed that the subscale for spiritual acceptance correlated significantly with binding potential but not with the other two subscales. CONCLUSIONS: This finding in normal male subjects indicated that the serotonin system may serve as a biological basis for spiritual experiences. The authors speculated that the several-fold variability in 5-HT(1A) receptor density may explain why people vary greatly in spiritual zeal.     

Influence of escitalopram treatment on 5-HT 1A receptor binding in limbic regions in patients with anxiety disorders

There is an increasing interest in the underlying mechanisms of the antidepressant and anxiolytic treatment effect associated with changes in serotonergic neurotransmission after treatment with selective serotonin (5-HT) reuptake inhibitors (SSRIs) in humans. The 5-HT(1A) receptor is known to play a crucial role in the pathophysiology of affective disorders, and altered 5-HT(1A) receptor binding has been found in anxiety patients. SSRI treatment raises the 5-HT level in the synaptic cleft and might change postsynaptic receptor densities. Therefore, our study in patients suffering from anxiety disorders investigated the effects of long-term treatment with escitalopram on the 5-HT(1A) receptor. A longitudinal positrone emission tomography (PET) study in 12 patients suffering from anxiety disorders was conducted. Two dynamic PET scans were performed applying the selective 5-HT(1A) receptor antagonist [carbonyl-(11)C]WAY-100635. Eight regions of interest were defined a priori (orbitofrontal cortex, amygdala, hippocampus, subgenual cortex, anterior and posterior cingulate cortex, dorsal raphe nucleus and cerebellum as reference). After the baseline PET scan, patients were administered escitalopram (average dose of 11.2+/-6.0 mg day(-1)) for a minimum of 12 weeks. A second PET scan was conducted after 109+/-27 days. 5-HT(1A) receptor binding potentials in 12 patients were assessed by PET applying the Simplified Reference Tissue Model.There was a significant reduction in the 5-HT(1A) receptor binding potential after a minimum of 12 weeks of escitalopram treatment in the hippocampus (P=0.006), subgenual cortex (P=0.017) and posterior cingulate cortex (P=0.034). The significance of the hippocampus region survived the Bonferroni-adjusted threshold for multiple comparisons. These PET data in humans in vivo demonstrate a reduction of the 5-HT(1A) binding potential after SSRI treatment.     

Reduced serotonin-1A receptor binding in social anxiety disorder.

BACKGROUND: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.     

Brain serotonin1A receptor binding in major depression is related to psychic and somatic anxiety.

BACKGROUND: The anxious phenotype of the 5-HT1A receptor knockout mouse and the anxiolytic properties of 5-HT1A agonists suggest that the 5-HT1A receptor modulates anxiety. We investigated the relationship of anxiety expressed in major depressive disorder (MDD) to regional 5-HT1A binding. METHODS: Positron emission tomography with [carbonyl-11C]WAY-100635 was used to estimate regional 5-HT1A binding potential (BP) in 28 medication-free MDD subjects. Stepwise linear regression assessed the predictive capacity of three anxiety components, derived from a larger MDD sample and termed psychic, somatic, and motoric anxiety, on regional 5-HT1A BP. RESULTS: Higher psychic (beta >or= .63) and lower somatic (beta 相似文献   

Serotonin 5-HT1A receptor binding in people with panic disorder: positron emission tomography study

BACKGROUND: The importance of the neurotransmitter serotonin (5-HT) in the pathophysiology of anxiety is well known. A key role for postsynaptic 5-HT(1A) receptors has recently been suggested in studies of genetic knockout mice. AIMS: To measure 5-HT(1A) receptor binding in patients with panic disorder in the untreated state and after recovery on treatment with selective serotonin reuptake inhibitors (SSRIs). METHOD: Nine symptomatic untreated patients with panic disorder, seven patients recovered on SSRI medication and nineteen healthy volunteers underwent a single positron emission tomography (PET) scan using the 5-HT(1A) tracer [(11)C]WAY-100635. RESULTS: In comparison with controls, both presynaptic and postsynaptic 5-HT(1A) receptor binding was reduced in untreated patients, with the most significant reductions being in the raphe, orbitofrontal cortex, temporal cortex and amygdala. In recovered patients presynaptic binding was reduced, but there was no significant reduction in postsynaptic binding. CONCLUSIONS: Panic disorder is associated with reduced 5-HT(1A) receptor availability, which is also known to have a key role in depression.     

Altered brain serotonin 5-HT1A receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [carbonyl11C]WAY-100635

CONTEXT: Previous studies have shown that women with anorexia nervosa (AN), when ill and after recovery, have alterations of serotonin (5-HT) neuronal activity and core eating disorder symptoms, such as anxiety. OBJECTIVE: To further characterize the 5-HT system in AN, we investigated 5-HT1A receptor activity using positron emission tomography imaging because this receptor is implicated in anxiety and feeding behavior. DESIGN, SETTING, AND PARTICIPANTS: To avoid the confounding effects of malnutrition, we studied 13 women who had recovered from restricting-type AN (mean age, 23.3 +/- 5.2 years) and 12 women who had recovered from bulimia-type AN (mean age, 28.6 +/- 7.3 years) (>1 year normal weight, regular menstrual cycles, no bingeing or purging). These subjects were compared with 18 healthy control women (mean age, 25.1 +/- 5.8 years).Intervention The 5-HT1A receptor binding was measured using positron emission tomography imaging and a specific 5-HT1A receptor antagonist, [carbonyl-11C]WAY-100635. MAIN OUTCOME MEASURE: Specific 5-HT1A receptor binding was assessed using the binding potential measure. Binding potential values were derived using both the Logan graphical method and compartmental modeling. The binding potential in a region of interest was calculated with the formula: binding potential = distribution volume of the region of interest minus distribution volume of the cerebellum. RESULTS: Women recovered from bulimia-type AN had significantly (P<.05) increased [11C]WAY-100635 binding potential in cingulate, lateral and mesial temporal, lateral and medial orbital frontal, parietal, and prefrontal cortical regions and in the dorsal raphe compared with control women. No differences were found for women recovered from restricting-type AN relative to controls. For women recovered from restricting-type AN, the 5-HT1A postsynaptic receptor binding in mesial temporal and subgenual cingulate regions was positively correlated with harm avoidance. CONCLUSIONS: We observed increased 5-HT1A receptor binding in women who had recovered from bulimia-type AN but not restricting-type AN. However, 5-HT1A receptor binding was associated with a measure of anxiety in women recovered from restricting-type AN. These data add to a growing body of evidence showing that altered serotonergic function and anxiety symptoms persist after recovery from AN. These psychobiological alterations may be trait related and may contribute to the pathogenesis of AN.     

Greater loss of 5-HT(2A) receptors in midlife than in late life

OBJECTIVE: Earlier work has shown markedly lower density of serotonin 2A (5-HT(2A)) receptors in elderly subjects than in young healthy subjects. In this study the authors used positron emission tomography (PET) and [(18)F]altanserin, a ligand with high affinity for the 5-HT(2A) receptor, to examine the relationship between 5-HT(2A) receptor density and age in more detail. METHOD: The 22 subjects ranged in age from 21 to 69 years (mean=43.4, SD=13.3) and were healthy comparison subjects in a study of depression. Regions of interest were determined on magnetic resonance images and were transferred to coregistered PET data. The data were derived from dynamic PET scanning and arterial sampling with resulting plasma activity data corrected for labeled metabolites. Compartmental modeling was used to estimate the radioligand distribution volume. By comparing the distribution volume (DV) of different regions to the cerebellum distribution volume, DV(ratio)-1, which is proportional to the binding potential, was calculated. RESULTS: The decrease in 5-HT(2A) binding was not linear but on average was approximately 17% per decade from age 20. The correlations between age and 5-HT(2A) DV(ratio)-1 were significant for the global measure and for the medial gyrus rectus, anterior cingulate, posterior medial prefrontal cortex, hippocampus, and occipital cortex. Most of the fall off in receptor binding occurred up through midlife, and there was less decrease in late life. There were no decreases in regional brain volumes of corresponding magnitudes. CONCLUSIONS: 5-HT(2A) receptor binding decreases dramatically in a variety of brain regions up through midlife.     

Higher postmortem prefrontal 5-HT2A receptor binding correlates with lifetime aggression in suicide.

BACKGROUND: In vivo studies find altered serotonin function associated with aggressive and suicidal behaviors. Postmortem studies also reveal serotonergic alterations in suicide subjects but have not reported on the relationship between aggression and the serotonin system. We measured 5-hydroxytryptamine 2A (5-HT(2A)) receptor binding in prefrontal cortex of suicide and nonsuicide subjects and explored the relationship between 5-HT(2A) receptor binding, lifetime aggression, and suicide. METHODS: The 5-HT(2A) receptor binding in coronal sections of prefrontal cortex was quantified by autoradiography with [(3)H] ketanserin in 37 suicide subjects and 73 nonsuicide subjects. The relationship between [(3)H] ketanserin binding and lifetime aggression, rated on the Brown-Goodwin Aggression History Scale, was assessed controlling for age and sex. RESULTS: In suicide subjects, lifetime aggression scores correlated positively with [(3)H] ketanserin binding in all prefrontal Brodmann areas examined, after adjusting for age and sex. This was not the case in nonsuicide subjects. We found no significant differences in aggression scores or [(3)H] ketanserin binding between the suicide subjects and nonsuicide subjects. CONCLUSIONS: The relationship between aggression and 5-HT(2A) receptor binding in suicide subjects, but not in nonsuicide subjects, may reflect differences in the regulation of the 5-HT(2A) receptor related to suicidal behavior and perhaps other proaggressive changes in brains of suicide subjects.     

Personality organization, five-factor model, and mental health

Otto Kernberg has developed a model of personality and psychological functioning centered on the concept of personality organization. The purpose of this study is to empirically examine the relationships between this model, the five-factor model, and mental health. The Personality Organization Diagnostic Form (Diguer et al., The Personality Organization Diagnostic Form-II (PODF-II), 2001), the NEO Five-Factor Inventory (Costa and McCrae, Revised NEO Personality Inventory (NEO-PI-R) and NEO Five-Factor Inventory (NEO-FFI) Professional Manual. 1992a), and the Health-Sickness Rating Scale (Luborsky, Arch Gen Psychiatry. 1962;7:407-417) were used to assess these constructs. Results show that personality organization and personality factors are distinct but interrelated constructs and that both contribute in similar proportion to mental health. Results also suggest that the integration of personality organization and factors can provide clinicians and researchers with an enriched understanding of psychological functioning.     

The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study

OBJECTIVE: In the cortex of animals, serotonin (5-HT) levels increase after several weeks of treatment with selective serotonin reuptake inhibitors (SSRIs). Studies using an intrasubject design to examine the effects of SSRI treatment on 5-HT(2A) receptors in the cortex of drug-free depressed patients are needed. In theory, agonist stimulation of 5-HT(2A) receptors could be relevant to SSRI treatment by promoting neuronal growth and survival as well as direct elevation of mood. The objective of this study was to evaluate the effect of 6 weeks of paroxetine treatment on 5-HT(2A) receptors in depressed patients. METHOD: After a medication-free period of at least 3 months, 19 depressed patients were treated for 6 weeks with paroxetine, 20 mg/day. The authors used [(18)F]setoperone and positron emission tomography to assess 5-HT(2A) receptor binding potential in the patients before and after treatment and in 19 age-matched healthy subjects. RESULTS: 5-HT(2A) binding potential declined with age in all cortical regions in the depressed and healthy subjects. There was a significant interaction between age and treatment effect on 5-HT(2A) binding potential in all cortical regions. Subjects aged 20 to 30 years had a 10% decrease in 5-HT(2A) binding potential after treatment, whereas subjects aged 30 to 40 had no change. No regional differences in 5-HT(2A) binding potential between depressed and healthy subjects were found. CONCLUSIONS: 5-HT(2A) receptors down-regulate in young depressed subjects after treatment with paroxetine, but this down-regulation attenuates with age. This suggests that over 6 weeks paroxetine treatment increases 5-HT agonism on 5-HT(2A) receptors in the cortex of young patients with depression.     

Selective heterologous regulation of 5-HT1A receptor-stimulated 35S GTPgammaS binding in the anterior cingulate cortex as a result of 5-HT2 receptor activation

Previous studies have shown that administration of the 5-HT(2) receptor agonist DOI to rats results in the heterologous desensitization of 5-HT(1A) receptor-mediated behavioral and neuroendocrine responses [Neuropsychopharmacology 19 (1998) 354; J. Neurosci. 21 (2001) 7919]. We hypothesized that the basis for these changes in 5-HT(1A) receptor function may involve changes in the capacity of the 5-HT(1A) receptor to activate G proteins. We examined the effect of chronic administration of DOI on the regulation of 5-HT(1A) receptor function at the level of receptor-G protein interaction using quantitative autoradiography of [(35)S]GTPgammaS binding stimulated by the 5-HT(1A) receptor agonist (+/-)8-OH-DPAT (1 microM). Repeated administration of DOI (1 mg/kg, s.c. once daily for 8 days) resulted in a marked down-regulation in 5-HT(2A) binding sites, as labeled by the antagonist radioligand [(3)H]ketanserin, throughout the cerebral cortex. Chronic DOI treatment also resulted in a significant and selective attenuation of 5-HT(1A) receptor-stimulated [(35)S]GTPgammaS binding in the anterior cingulate cortex (vehicle-treated: 74+/-7.7% above basal; DOI-treated: 43+/-4.6% above basal). Interestingly, 5-HT(1A) receptor-stimulated [(35)S]GTPgammaS binding was not altered in the dorsal or median raphe, or in the limbic structures and other cortical regions examined. The decrease in 5-HT(1A) receptor-stimulated [(35)S]GTPgammaS binding in anterior cingulate cortex was not due to a decrease in 5-HT(1A) receptor number, indicating that the capacity of the 5-HT(1A) receptor to activate G proteins is attenuated in this cortical area following repeated DOI treatment. The heterologous regulation of 5-HT(1A) receptor function by chronic 5-HT(2) receptor activation in the anterior cingulate cortex raises interesting questions as to how the regulatory interaction between these serotonin receptor subtypes influences cognition, memory and emotion.     

Exaggerated 5-HT1A but normal 5-HT2A receptor activity in individuals ill with anorexia nervosa.

BACKGROUND: Many studies have found disturbances of serotonin (5-HT) activity in anorexia nervosa (AN). Because little is known about 5-HT receptor function in AN, positron emission tomography (PET) imaging with 5-HT receptor-specific radioligands was used to characterize 5-HT1A and 5-HT2A receptors. METHODS: Fifteen women ill with AN (ILL AN) were compared with 29 healthy control women (CW); PET and [11C]WAY100635 were used to assess binding potential (BP) of the 5-HT1A receptor, and [18F]altanserin was used to assess postsynaptic 5-HT2A receptor BP. [15O] water and PET were used to assess cerebral blood flow. RESULTS: The ILL AN women had a highly significant (30%-70%) increase in [11C]WAY100635 BP in prefrontal and lateral orbital frontal regions, mesial and lateral temporal lobes, parietal cortex, and dorsal raphe nuclei compared with CW. The [18F]altanserin BP was normal in ILL AN but was positively and significantly related to harm avoidance in suprapragenual cingulate, frontal, and parietal regions. Cerebral blood flow was normal in ILL AN women. CONCLUSIONS: Increased activity of 5-HT1A receptor activity may help explain poor response to 5-HT medication in ILL AN. This study extends data suggesting that 5-HT function, and, specifically, the 5-HT2A receptor, is related to anxiety in AN.     

Brain serotonin 1A receptor binding in bulimia nervosa.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are the first choice for the pharmacologic treatment of bulimia nervosa, but there are no published data on the putative altered serotonin (5-HT) receptor characteristics in patients with bulimia. Experimental studies suggest that the therapeutic antidepressant effect of SSRIs is mediated via 5-HT(1A) receptors. The aim of this study was to measure brain 5-HT(1A) receptor binding among nonmedicated patients with bulimia nervosa. METHODS: Positron emission tomography (PET) with a selective 5-HT(1A) ligand, [11C]WAY-100635, was performed on eight unmedicated patients with bulimia and 10 healthy comparison subjects. RESULTS: The binding potential values were greater in patients than in control subjects in all brain regions studied. The most robust differences were observed in the angular gyrus, the medial prefrontal cortex, and the posterior cingulate cortex. CONCLUSIONS: These results suggest that brain 5-HT(1A) receptor binding is increased in several cortical areas in patients with bulimia nervosa during their state of impulsive binge eating.