Yung-yu Huang

Altered serotonin 1A binding in major depression: a [carbonyl-C-11]WAY100635 positron emission tomography study.

BACKGROUND Serotonin 1A receptors (5-HT(1A)) are implicated in the pathophysiology of major depressive disorder (MDD) and in the action of selective serotonin reuptake inhibitors (SSRI). SSRI desensitize 5-HT(1A) and down-regulate 5-HT transporters (5-HTT) with the latter persisting for weeks after discontinuation of SSRI. MDD subjects are more likely to be homozygous for the functional 5-HT(1A) G(-1019) allele of the promoter polymorphism and are postulated to have higher 5-HT(1A) than healthy volunteers (controls). We measure 5-HT(1A) in MDD, assess the effects of antidepressant exposure (AE), and examine the role of the C(-1019)G polymorphism. METHODS Genotyped and determined 5-HT(1A) binding potential (BP) by positron emission tomography (PET) using [carbonyl-C-11]-WAY-100635 in 28 medication-free MDD subjects during a current major depressive episode and 43 controls. RESULTS No difference in BP between controls and MDD subjects (p = .235). There was a difference in BP comparing the controls, antidepressant naive (AN) MDD subjects, and subjects with AE across all regions (p = .013). Post hoc testing reveals higher BP in AN compared to controls (p = .008) and to AE (p = .007). The GG genotype is overrepresented in MDD subjects (p = .059), and BP appears higher with the G allele. CONCLUSIONS AN have higher 5-HT(1A) than controls and AE suggesting a model of depression characterized by an over expression of autoinhibitory somatodendritic 5-HT(1A) receptors, perhaps due to the higher expressing G allele, that may result in reduced terminal field 5-HT release. AE appears to have long-term effects on 5-HT(1A).

Aggressivity, suicide attempts, and depression: relationship to cerebrospinal fluid monoamine metabolite levels

BACKGROUND We have proposed a stress-diathesis model for suicidal behavior, in which major depression is a stressor and the diathesis is shared with aggression. Neurotransmitter correlates of the stress or diathesis have not been adequately evaluated by previous studies, because they did not simultaneously examine the relationship of multiple neurotransmitters to all three psychopathologies in the same population. In the present study we investigated the relationship of monoamine metabolites to aggressivity, suicidal behavior, and depression in patients with mood disorders. METHODS Ninety-three drug-free subjects with a major depressive episode underwent lumbar puncture and psychiatric evaluation. Cerebrospinal fluid CSF levels of 5hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA) and methoxy-hydroxy-phenylglycol (MHPG) were assayed. The relationships between monoamine metabolites and clinical variables were statistically evaluated. RESULTS Higher lifetime aggressivity correlated significantly with lower CSF 5-HIAA. Lower CSF 5-HIAA and greater suicidal intent were found in high-lethality suicide attempters compared with low-lethality suicide attempters. Low-lethality attempters did not differ biologically from nonattempters. No correlation between CSF HVA and any of the psychopathological variables was found. Only aggression showed a trend statistically in correlating positively with CSF MHPG levels. CONCLUSIONS Lower CSF 5-HIAA concentration was independently associated with severity of lifetime aggressivity and a history of a higher lethality suicide attempt and may be part of the diathesis for these behaviors. The dopamine and norepinephrine systems do not appear to be as significantly involved in suicidal acts, aggression, or depression. The biological correlates of suicide intent warrant further study.

An Association between a Functional Polymorphism in the Monoamine Oxidase A Gene Promoter, Impulsive Traits and Early Abuse Experiences

Monoamine oxidase A (MAOA) activity is altered in mood disorders and lower activity associated with aggressive behavior. The gene has a functional polymorphism with a variable number tandem repeat (VNTR) in the upstream regulatory region (MAOA-uVNTR). In this study, we examined possible associations between the MAOA-uVNTR polymorphism and mood disorders, suicidal behavior, aggression/impulsivity, and effects of reported childhood abuse. In total, 663 unrelated subjects with a psychiatric disorder and 104 healthy volunteers were genotyped for the 30 base pair functional VNTR. A novel repeat variation was identified. No statistically significant associations were found between this functional MAOA-uVNTR polymorphism and mood disorders or suicide attempts. However, the lower expression allele was associated with a history of abuse before 15 years of age in male subjects and with higher impulsivity in males but not females. Our results suggest that the lower expression of the MAOA-uVNTR polymorphism is related to a history of early abuse and may sensitize males, but not females, to the effects of early abuse experiences on impulsive traits in adulthood. The polymorphism may be a marker for impulsivity that in turn may contribute to the risk for abuse. This trait could then be further aggravated by abuse.

Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons.

The gut contains a large 5-HT pool in enterochromaffin (EC) cells and a smaller 5-HT pool in the enteric nervous system (ENS). During development, enteric neurons are generated asynchronously. We tested hypotheses that serotonergic neurons, which arise early, affect development/survival of later-born dopaminergic, GABAergic, nitrergic, and calcitonin gene-related peptide-expressing neurons and are essential for gastrointestinal motility. 5-HT biosynthesis depends on tryptophan hydroxylase 1 (TPH1) in EC cells and on TPH2 in neurons; therefore, mice lacking TPH1 and/or TPH2 distinguish EC-derived from neuronal 5-HT. Deletion of TPH2, but not TPH1, decreased myenteric neuronal density and proportions of dopaminergic and GABAergic neurons but did not affect the extrinsic sympathetic innervation of the gut; intestinal transit slowed in mice lacking TPH2 mice, but gastric emptying accelerated. Isolated enteric crest-derived cells (ENCDCs) expressed the serotonin reuptake transporter (SERT) and 15 subtypes of 5-HT receptor. Addition of 5-HT to cultures of isolated ENCDCs promoted total and dopaminergic neuronal development. Rings of SERT-immunoreactive terminal axons surrounded myenteric dopaminergic neurons and SERT knock-out increased intestinal levels of dopamine metabolites, implying that enteric dopaminergic neurons receive a serotonergic innervation. Observations suggest that constitutive gastrointestinal motility depends more on neuronal than EC cell serotonin; moreover, serotonergic neurons promote development/survival of some classes of late-born enteric neurons, including dopaminergic neurons, which appear to innervate and activate in the adult ENS.

Higher 5-HT1A receptor binding potential during a major depressive episode predicts poor treatment response: preliminary data from a naturalistic study.

Serotonin 1A (5-HT1A) binding potential (BP) as assessed by positron emission tomography (PET) is higher in major depressive disorder (MDD) in association with the higher expressing GG genotype of the 5-HT1A C-1019G polymorphism. We hypothesize that higher 5-HT1A BP and the GG genotype predict remission failure on antidepressant treatment. We determined 5-HT1A BP by PET and 5-HT1A C-1019G genotype in 43 controls and 22 medication-free MDD subjects. MDD was treated naturalistically and remission was defined as >50% reduction and a score of ⩽10 on the 24 item Hamilton Scale 1 year after initiation of treatment after scanning. Despite equivalent treatment, nonremitters have higher pretreatment cortical BP and the GG genotype is over-represented compared with remitters. Higher 5-HT1A BP, perhaps due to greater gene expression, may predict antidepressant medication nonremission. The findings should be tested in a controlled prospective treatment study.

Human 5-HT1A receptor C(−1019)G polymorphism and psychopathology

Dysfunction of the serotonin (5-HT1A) receptor (5-HTR1A) has been implicated in mood disorders, anxiety disorders, psychosis and the action of antidepressants. A common C(-1018)G [C(-1019)G] functional polymorphism in the promoter region of the human 5-HT1A receptor gene has been reported, which may be useful in identifying psychopathology associated with altered function of the human 5-HT1A receptor. We studied the relationship of this polymorphism to psychopathology and 5-HT1A binding in prefrontal cortex. The 5-HT1A receptor genotype for the C(-1019)G polymorphism was typed in 696 unrelated psychiatric subjects, 107 unrelated healthy volunteers, and in post-mortem brain samples from 241 cases. 5-HT1A receptor binding was assayed in post-mortem prefrontal cortex using [3H]8-OH-DPAT, and specific binding determined by 1 microM 5-HT. An association of genotype distribution and allele frequency of the 5-HTR1A C(-1019)G locus was observed in schizophrenia (chi2=9.51, d.f.=2, p=0.009; chi2=9.52, d.f.=1, p=0.002; Armitages trend test: chi2=9.07, d.f.=1, p=0.003), in substance use disorder (chi2=8.41, d.f.=2, p=0.015; chi2=8.35, d.f.=1, p=0.004; Armitages trend test: chi2=6.27, d.f.=1, p=0.0012), and in panic attack (chi2=6.31, d.f.=2, p=0.043; chi2=6.14, d.f.=1, p=0.013; Armitages trend test: chi2=6.27, d.f.=1, p=0.012). An association of the 5-HTR1A C(-1019)G locus with schizophrenia, substance use disorder, and panic attack was suggested by our results. In post-mortem brain samples, 5-HT1A receptor binding in prefrontal cortex and suicide were not associated with genotype. The relationship does not appear to be explained by binding differences, although we cannot rule out altered receptor affinity and transduction.

Relationship of psychopathology to the human serotonin1B genotype and receptor binding kinetics in postmortem brain tissue

Knockout of the 5-HT1B gene in mice results in increased aggression, as well as alcohol and cocaine consumption. Given the clinical association of aggression, suicide, alcoholism, and substance abuse, we studied relationship of psychopathology to the human 5-HT1B receptor gene (N = 178) and postmortem human 5-HT1B receptor binding (N = 96) in the brain. The sample comprised: 71 suicide victims, 107 nonsuicides, 45 with a history of major depression and 79 without, 64 with a history of a alcoholism or substance abuse and 60 without, as well as 36 with a history of pathological aggression and 42 without. Single-strand conformational polymorphism (SSCP) analysis and DNA sequencing techniques were used to screen the coding region of the human 5-HT1B receptor gene in genomic DNA isolated from postmortem human brain tissue. Two common polymorphisms were identified in the 5-HT1B receptor gene, involving a silent C to T substitution at nucleotide 129 and a silent G to C substitution at nucleotide 861 of the coding region. These polymorphisms were found with the same frequency in the suicide and the nonsuicide groups and in those with and without a history of major depression, alcoholism, or pathological aggression. The binding indices (Bmax and KD of the 5-HT1B receptor in prefrontal cortex also did not differ in suicides and controls, major depression, alcoholism, and cases with a history of pathological aggression. The C129 or G861 allele had 20% fewer 5-HT1B receptor compared to the 129T or 861C allele. We did not identify a relationship between suicide, major depression, alcoholism, or pathological aggression with 5-HT1B receptor binding indices or genotype.

Substance abuse disorder and major depression are associated with the human 5-HT1B receptor gene (HTR1B) G861C polymorphism.

The 5-HT1B receptor has been implicated in several psychopathologies, including pathological aggression, alcoholism and suicide. To test these and related potential genetic relationships in a single population, the human 5-HT1B receptor (h5-HTR1B) genotype for the G861C polymorphism was determined in 394 psychiatric patients and 96 healthy volunteers. Structured clinical interviews generated DSM III-R diagnoses. No significant association of the genotype or allele frequencies of the h5-HTR1B G861C locus was observed with diagnoses of alcoholism, bipolar disorder, schizophrenia or a history of a suicide attempt. Exploratory analyses indicated an association of the genotype and allele frequencies of the h5-HTR1B G861C locus with a history of substance abuse disorder (χ2=9.51, df=2, p=0.009; χ2=7.31, df=1, p=0.007, respectively) and with a diagnosis of a major depressive episode (χ2=6.83, df=2, p=0.033; χ2=5.81, df=1, p=0.016, respectively). Significant gene dose effects on the risk for substance abuse disorder and a major depressive episode were observed with the 861C allele (Armitage linearity tendency test: χ2=7.20, df=1, p=0.008; χ2=6.80, df=1, p=0.009, respectively). Substance abuse disorder and major depression appear to be associated with the h5-HTR1B G861C locus in the patient population, but other psychopathologies such as bipolar disorder, schizophrenia, alcoholism, and suicide attempts were not found to be associated with this polymorphism. This preliminary result will need replication, given the limitations of association studies.

Maternal and Offspring Pools of Osteocalcin Influence Brain Development and Functions

The powerful regulation of bone mass exerted by the brain suggests the existence of bone-derived signals modulating this regulation or other functions of the brain. We show here that the osteoblast-derived hormone osteocalcin crosses the blood-brain barrier, binds to neurons of the brainstem, midbrain, and hippocampus, enhances the synthesis of monoamine neurotransmitters, inhibits GABA synthesis, prevents anxiety and depression, and favors learning and memory independently of its metabolic functions. In addition to these postnatal functions, maternal osteocalcin crosses the placenta during pregnancy and prevents neuronal apoptosis before embryos synthesize this hormone. As a result, the severity of the neuroanatomical defects and learning and memory deficits of Osteocalcin(-/-) mice is determined by the maternal genotype, and delivering osteocalcin to pregnant Osteocalcin(-/-) mothers rescues these abnormalities in their Osteocalcin(-/-) progeny. This study reveals that the skeleton via osteocalcin influences cognition and contributes to the maternal influence on fetal brain development.

Non-suicidal self-injurious behavior, endogenous opioids and monoamine neurotransmitters

BACKGROUND Self-inflicted injury, including cutting or burning, is the most frequent reason for psychiatric visits to medical emergency departments. This behavior, particularly when there is no apparent suicidal intent, is poorly understood from both biological and clinical perspectives. OBJECTIVE To examine the role of endogenous opioids and monoamine neurotransmitters in non-suicidal self-injury (NSSI). METHODS We compared cerebrospinal fluid (CSF) levels of endogenous opioids, 5 hydroxyindolacetic acid (5-HIAA) and homovanillic acid (HVA) in individuals with a history of repetitive non-suicidal self-injury with a diagnostically-matched group of individuals who had never engaged in non-suicidal self-injury. History of suicidal behavior, demographic background and psychopathology was assessed. All patients were diagnosed with a Cluster B personality disorder (i.e. borderline, antisocial, narcissistic or histrionic) (N=29) and had a history of at least one suicide attempt. Fourteen participants had a history of repeated non-suicidal self-injurious behavior (NSSI) in adulthood and 15 did not (no NSSI). RESULTS The NSSI group had significantly lower levels of CSF beta-endorphin and met-enkephalin when compared with the non-NSSI group. CSF dynorphin, HVA and 5-HIAA levels did not differ. Severity of depression, hopelessness and overall psychopathology was greater in the NSSI group. CONCLUSION beta-endorphin and met-enkephalin, opioids acting upon receptors involved in mediating stress-induced and physical pain analgesia respectively, are implicated in NSSI. Serotonergic and dopaminergic dysfunctions do not appear to be related to NSSI. Based on our findings, we propose a model of non-suicidal self-injury. Our results suggest that drugs acting on the opioid system warrant exploration as pharmacological treatments for NSSI.