Does sodium oxybate inhibit brain dopamine release in humans? An exploratory neuroimaging study.

Objective: To establish in an exploratory neuroimaging study whether γ-hydroxybutyrate (sodium oxybate [SO]), a sedative, anti-narcoleptic drug with abuse potential, transiently inhibits striatal dopamine release in the human.

Methods: Ten healthy participants (30 years; 6M, 4F) and one participant with narcolepsy received a baseline positron emission tomography scan of [C-11]raclopride, a D2/3 dopamine receptor radioligand sensitive to dopamine occupancy, followed approximately one week later by an oral sedative 3g dose of SO and two [C-11]raclopride scans (1 h, 7 h post SO). Plasma SO levels and drowsiness duration were assessed.

Chronic LiCl pretreatment suppresses thrombin-stimulated intracellular calcium mobilization through TRPC3 in astroglioma cells.

Objectives: Transient receptor potential canonical type 3 (TRPC3) channels are activated in B lymphoblast cell lines from patients with bipolar disorder (BD), and its expression is reduced by chronic lithium treatment, implicating TRPC3 in the intracellular calcium (Ca ) dyshomeostasis of BD. Thrombin, via a protease-activated receptor, moderates Ca signaling and TRPC3 in astrocytes, and also cell proliferation. We examined whether lithium pretreatment attenuates thrombin-stimulated TRPC3 expression and function in astrocytes, and levels of the calcium-binding peptide, S100B, which is expressed mainly in these cells.

Differential cardiovascular and hypothalamic pituitary response to amphetamine in male pathological gamblers versus healthy controls.

Cardiovascular and hypothalamic pituitary axis (HPA) disturbances have been observed in individuals who are pathological gamblers (PGs). These may partly derive from chronic exposure to gambling. Response to amphetamine (AMPH) may reveal such disturbances while controlling for differential conditioned responses to gambling in PGs vs healthy controls (HCs).

CACNA1C SNP rs1006737 associates with bipolar I disorder independent of the Bcl-2 SNP rs956572 variant and its associated effect on intracellular calcium homeostasis.

Objectives: Intracellular calcium (Ca(2+)) dyshomeostasis (ICDH) has been implicated in bipolar disorder (BD) pathophysiology. We previously showed that SNP rs956572 in the B-cell CLL/lymphoma 2 (Bcl-2) gene associates with elevated B lymphoblast (BLCL) intracellular Ca(2+) concentrations ([Ca(2+)]B) differentially in BD-I. Genome-wide association studies strongly support the association between BD and the SNP rs1006737, located within the L-type voltage-dependent Ca(2+) channel α1C subunit gene (CACNA1C).

Increased bcl-2 Protein Levels in Rat Primary Astrocyte Culture Following Chronic Lithium Treatment.

Background: B cell CLL/lymphoma 2 protein, bcl-2, is an important anti-apoptotic factor that has been implicated in lithium's neuroprotective effect. However, most studies have focused on assessing the effects of lithium in neurons, ignoring examination of bcl-2 in astrocytes, which also influence neuronal survival and are affected in bipolar disorder. The aim of this study was to evaluate whether chronic lithium treatment also elevates bcl-2 expression in astrocytes compared with neuronal and mixed neuron-astrocyte cultures.

Association of the iPLA2β gene with bipolar disorder and assessment of its interaction with TRPM2 gene polymorphisms.

Altered intracellular calcium homeostasis and oxidative stress are involved in the pathophysiology of bipolar disorder (BD)-I. To explore the genes contributing to these abnormalities, we examined the association with BD of the iPLA2β (PLA2G6), a signaling enzyme that mobilizes the arachidonic acid signaling cascade and activates oxidative stress, and assessed whether it interacts genetically with type 2 transient receptor potential channel gene (TRPM2), an oxidative stress-responsive calcium channel implicated both functionally and genetically in BD-I. Two tag single nucleotide polymorphisms rs4375 and rs3788533 in iPLA2β were genotyped in 446 White case-control individuals and 296 BD families using a 5'-nuclease TaqMan assay.

Effect of oxidative stress on TRPM2 and TRPC3 channels in B lymphoblast cells in bipolar disorder.

Objectives: Recent findings implicate the calcium-permeable nonselective ion channels transient receptor potential (TRP) melastatin subtype 2 (TRPM2) and canonical subtype 3 (TRPC3) in the pathogenesis of bipolar disorder (BD). These channels are involved in calcium and oxidative stress signaling, both of which are disrupted in BD. Thus, we sought to determine if these channels are differentially affected by oxidative stress in cell lines of BD patient origin.

Inhibition of glycogen synthase kinase-3 enhances the differentiation and reduces the proliferation of adult human olfactory epithelium neural precursors.

The olfactory epithelium (OE) contains neural precursor cells which can be easily harvested from a minimally invasive nasal biopsy, making them a valuable cell source to study human neural cell lineages in health and disease. Glycogen synthase kinase-3 (GSK-3) has been implicated in the etiology and treatment of neuropsychiatric disorders and also in the regulation of murine neural precursor cell fate in vitro and in vivo. In this study, we examined the impact of decreased GSK-3 activity on the fate of adult human OE neural precursors in vitro.

Bcl-2 SNP rs956572 associates with disrupted intracellular calcium homeostasis in bipolar I disorder.

Objectives: Disrupted intracellular calcium (Ca(2+) ) homeostasis (ICH) related to mitochondrial and/or endoplasmic reticulum (ER) dysfunction has been implicated in bipolar disorder (BD). The anti-apoptotic protein B-cell CLL/lymphoma 2 (Bcl-2), encoded in a putative BD susceptibility locus, modulates ER-Ca(2+) dynamics. Recently, an intronic single-nucleotide polymorphism (SNP) in the Bcl-2 gene, rs956572, was suggested as a functionally active SNP that influences its messenger RNA (mRNA) and protein level as well as human gray matter volume.

Decreased cerebral cortical serotonin transporter binding in ecstasy users: a positron emission tomography/[(11)C]DASB and structural brain imaging study.

Animal data indicate that the recreational drug ecstasy (3,4-methylenedioxymethamphetamine) can damage brain serotonin neurons. However, human neuroimaging measurements of serotonin transporter binding, a serotonin neuron marker, remain contradictory, especially regarding brain areas affected; and the possibility that structural brain differences might account for serotonin transporter binding changes has not been explored. We measured brain serotonin transporter binding using [(11)C] N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine in 50 control subjects and in 49 chronic (mean 4 years) ecstasy users (typically one to two tablets bi-monthly) withdrawn from the drug (mean 45 days).

Differential modulation of intracellular Ca2+ responses in B lymphoblasts by mood stabilizers.

Irregularities of intracellular calcium (Ca2+) homeostasis have been implicated in the pathophysiology of bipolar disorder (BD). Findings that chronic ex-vivo treatment with lithium modifies lysophosphatidic acid (LPA)-stimulated Ca2+ responses in B lymphoblast cell lines (BLCLs) from BD-I patients and healthy controls, and differentially decreases levels of the type-3 canonical transient receptor potential Ca2+-permeable channel in BLCLs from BD-I patients, support the view that the amelioration of these abnormalities is important in the therapeutic action of lithium. To determine whether other clinically efficacious mood stabilizers share these effects, LPA (100 mum)- and thapsigargin (TG, 200 nm)-stimulated Ca2+ responses were determined in BLCLs from BD-I patients and healthy controls treated acutely (24 h) and chronically (7 d) ex vivo with therapeutically relevant concentrations of lithium (0.

TRPC3 protein is expressed across the lifespan in human prefrontal cortex and cerebellum.

The canonical transient receptor potential type 3 (TRPC3) channel is a non-selective, voltage-independent cation channel that is expressed in both excitable and non-excitable cells. As little is known regarding its presence in human brain and the influence of age on its expression, we examined TRPC3 protein expression by immunoblotting in postmortem prefrontal cortex and cerebellum obtained from subjects (8 days to 83 years) with no history of psychiatric or neurological disorder. The expression of TRPC3 protein in the prefrontal cortex (Brodmann area A9/A10) of the neonates/infants (<2 y) was significantly higher (25%) than that in the adolescent to adult (11y-83y) age group, whereas cerebellar TRPC3 levels showed no age-related changes.

TRPM2 variants and bipolar disorder risk: confirmation in a family-based association study.

Objective: Recent case-control studies implicate the transient receptor potential melastatin 2 (TRPM2) channel in conferring risk for bipolar disorder (BD), though the risk variants differed. As confounding effects of population structure could not be unequivocally ruled out as the basis for the discordance, we tested the association of TRPM2 with BD in a family design, which is immune to population stratification, for those TRPM2 single nucleotide polymorphisms (SNPs) previously reported as associated with BD.

Methods: The exon 11 SNP (rs1556314) and four informative intronic SNPs (rs1785437, rs1618355, rs933151, and rs749909) were genotyped in 300 BD families by TaqMan allelic discrimination and results were analyzed using chi(2) test, transmission disequilibrium test, and pedigree-based association.

Elevated serotonin transporter binding in depressed patients with Parkinson's disease: a preliminary PET study with [11C]DASB.

This study investigated whether abnormalities in serotonin transporter binding occur in Parkinson's disease (PD) patients with concurrent depression. We estimated serotonin transporter levels in seven clinically depressed early-stage PD patients and in seven healthy matched-control subjects during a single positron emission tomography (PET) scan with the serotonin transporter radioligand, [(11)C]DASB. Depressed PD patients displayed a wide-spread increase (8-68%) in [(11)C]DASB specific binding outside of the striatum, which was significant in dorsolateral (37%) and prefrontal (68%) cortices.

Analysis of BDNF Val66Met allele-specific mRNA levels in bipolar disorder.

We have previously reported an association between the BDNF Val66Met polymorphism and bipolar disorder (BD). However, the possibility that genomic imprinting in BDNF gene affects risk for BD has not been investigated. To examine the possibility of genomic imprinting in the BDNF gene in BD, we analyzed the parent-of-origin effect (POE) and differential expression of the BDNF Val66Met alleles in BD.

Further support for association of the mitochondrial complex I subunit gene NDUFV2 with bipolar disorder.

Background: The nuclear-encoded mitochondrial complex I subunit gene, NDUFV2, has been implicated in the pathogenesis of bipolar disorder (BD) in Japanese by virtue of association of variants in its promoter with BD and decreased NDUFV2 messenger ribonucleic acid (mRNA) levels in B lymphoblasts (BLCL) in BD patients compared to controls. We sought to determine if these same changes occur in non-Japanese populations and, if so, their relationship to altered basal intracellular Ca(2+) ([Ca(2+)](B)) in BLCL from BD patients.

Methods: Bipolar disorder patients and healthy subjects included 298 subjects of European Caucasian descent.

Hyperactive intracellular calcium dynamics in B lymphoblasts from patients with bipolar I disorder.

Substantial evidence implicates abnormalities of intracellular calcium (Ca2+) dynamics in the pathophysiology of bipolar disorder (BD). However, the precise mechanisms underlying such disturbances are poorly understood. To further elaborate the nature of altered intracellular Ca2+ signalling dynamics that occur in BD, we examined receptor- and store-operated Ca2+ responses in B lymphoblast cell lines (BLCLs), which have been found in earlier studies to 'report' BD-associated disturbances.

Impaired endoplasmic reticulum stress response in B-lymphoblasts from patients with bipolar-I disorder.

Background: Aberrant intracellular calcium (Ca2+) signaling in patients with bipolar-I disorder (BD-I) suggests disturbed endoplasmic reticulum (ER) function in BD. We examined whether the ER stress response is altered in BD-I patients and the relationship to basal intracellular Ca2+ levels ([Ca2+]B), in B lymphoblasts (BLCLs) from BD-I patients.

Methods: Endoplasmic reticulum stress-induced X-box binding protein 1 (XBP1), C/EBP homologous protein (CHOP), and GRP78 expression in BLCLs from BD-I subjects stratified on elevated or normal [Ca2+]B and control subjects were determined by real-time quantitative reverse transcription polymerase chain reaction.

Characterization of the transient receptor potential channels mediating lysophosphatidic acid-stimulated calcium mobilization in B lymphoblasts.

Altered 1-oleoyl-lysophosphatidic acid (LPA, 100 microM)-stimulated calcium responses occur in B-lymphoblast cell lines from bipolar disorder patients, but the mechanism(s) involved is uncertain. Lysophosphatidic acid shares a structurally similar fatty acid side chain with the diacylglycerol analogue, 1-oleoyl-2-acetyl-sn-glycerol (OAG), a known activator of subtypes 3, 6 and 7 of the canonical transient receptor potential (TRPC) cation channel subfamily. Accordingly, the objective of this study was to determine whether the LPA-stimulated calcium response in B-lymphoblasts is mediated, in part, through this TRPC channel subfamily.

Serum calcium-independent phospholipase A2 activity in bipolar affective disorder.

Objective: Phospholipases A2 (PLA2) are a family of enzymes involved in membrane phospholipid metabolism and cell signalling. The gene encoding one form, type VI calcium-independent phospholipase A2, is located in a region of DNA that may contain a gene important in the aetiology of psychosis. Moreover, the activity of calcium-independent PLA2 is reported to be elevated in the blood and brain of patients with schizophrenia.

Cytoprotection by lithium and valproate varies between cell types and cellular stresses.

Despite much evidence that lithium and valproate, two commonly used mood stabilizers, exhibit neuroprotective properties against an array of insults, the pharmacological relevance of such effects is not clear because most of these studies examined the acute effect of these drugs in supratherapeutic doses against insults which were of limited disease relevance to bipolar disorder. In the present study, we investigated whether lithium and valproate, at clinically relevant doses, protects human neuroblastoma (SH-SY5Y) and glioma (SVG and U87) cells against oxidative stress and endoplasmic reticulum stress in a time-dependent manner. Pretreatment of SH-SY5Y cells for 7 days, but not 1 day, with 1 mM of lithium or 0.

Galpha(s) sensitizes human SH-SY5Y cells to apoptosis independently of the protein kinase A pathway.

Disturbances in Galpha(s-L) levels and function have been implicated in the pathophysiology of bipolar disorder, but the role of these changes in the development of the illness is not clear. In view of the critical role of Galpha(s)-mediated cAMP signaling in regulating cell survival, we investigated the potential role of Galpha(s-L) in modulating susceptibility to cellular stressors in human SH-SY5Y neuroblastoma cells. Overexpression of Galpha(s-L) to a level twice that of the vector-transfected cells did not directly affect cell viability but significantly increased the sensitivity to induction of cell death by serum deprivation and other apoptotic stimuli, including staurosporine, H(2)O(2), and tunicamycin.

Association of the putative susceptibility gene, transient receptor potential protein melastatin type 2, with bipolar disorder.

Disturbed intracellular calcium (Ca(2+)) homeostasis has been implicated in bipolar disorder (BD). Reduced mRNA levels of the transient receptor potential Ca(2+) permeable channel melastatin type 2, TRPM2, in B lymphoblast cell lines (BLCL) from bipolar I disorder (BD-I) patients showing elevated basal intracellular Ca(2+) ([Ca(2+)](B)), an index of altered intracellular Ca(2+) homeostasis, along with its location within a putative BD susceptibility locus (21q22.3), implicates the involvement of this gene in the Ca(2+) abnormalities and the genetic diathesis to BD.

Reduced vasodilatory response to methylnicotinate in schizophrenia as assessed by laser Doppler flowmetry.

The normal vasodilatory response to topically applied methylnicotinate has been reported to be absent or reduced in patients with schizophrenia, a finding thought to be related to aberrant phospholipid metabolism. Previous studies have however failed to measure vasodilation using a direct and objective method. In addition, it is unknown whether methylnicotinate insensitivity is specific to schizophrenia.