The neurobiology of bipolar disorder: findings using human postmortem central nervous system tissue.

Objective: Postmortem brain studies have been undertaken to understand changes in the molecular architecture of the central nervous system (CNS) of subjects with bipolar disorder. These studies, along with a limited number of functional neuroimaging studies, have been reviewed to provide information on the neurobiology underlying the disorder.

Method: Findings from the study of postmortem brain tissue and neuroimaging were reviewed if their focus was on the molecular architecture of the human CNS to identify future lines of research required to understand the underlying pathology of bipolar disorder.

Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial.

Background: Alzheimer disease (AD) may be caused by the toxic accumulation of beta-amyloid (Abeta).

Objective: To test this theory, we developed a clinical intervention using clioquinol, a metal-protein-attenuating compound (MPAC) that inhibits zinc and copper ions from binding to Abeta, thereby promoting Abeta dissolution and diminishing its toxic properties.

Methods: A pilot phase 2 clinical trial in patients with moderately severe Alzheimer disease.

Increased levels of apolipoprotein E in the frontal cortex of subjects with schizophrenia.

Background: It is unclear whether altered expression of a specific isoform of apolipoprotein E (apoE) is associated with the pathology of schizophrenia.

Methods: To address whether apoE may be involved in the pathology of schizophrenia, we measured the genotypic and allelic frequency of polymorphisms in its gene and transcriptional regulatory region in DNA from Brodmann's area (BA) 9 obtained postmortem from schizophrenic and control subjects as well as its levels in the same tissue using Western blot analysis.

Results: The genotypic or allelic frequencies of any polymorphism studied did not vary between diagnostic cohorts.

Spectrum of saccade system function in Alzheimer disease.

Background: In Alzheimer disease (AD), tests of "first-order capabilities," such as reaction time or motor ability, might measure central nervous system integrity or disability more reliably than those of abstract, conceptual, or cognitive behavior. Saccade system impairments are present in AD, but their sensitivity or specificity remains unevaluated.

Objectives: To determine sensitivity and specificity of saccade measures for AD, precise impairments in AD, and the relationship between dementia severity and saccade system function.

Muscarinic receptors in schizophrenia.

An increasing body of evidence suggests that the muscarinic receptors may present a potential therapeutic target for the treatment of schizophrenia. This argument is supported by studies using postmortem CNS tissue and a neuroimaging study that have shown there are regionally specific decreases in selective muscarinic receptors in the CNS of subjects with schizophrenia. This raises the possibility that drugs specific to individual muscarinic receptors could have beneficial effects on the symptoms of schizophrenia, a posit supported by studies in receptor knockout/knockdown mice where it has been shown that specific behaviours affected by schizophrenia are also abnormal in mice lacking a single muscarinic receptor.

Neurotoxic, redox-competent Alzheimer's beta-amyloid is released from lipid membrane by methionine oxidation.

The amyloid beta peptide is toxic to neurons, and it is believed that this toxicity plays a central role in the progression of Alzheimer's disease. The mechanism of this toxicity is contentious. Here we report that an Abeta peptide with the sulfur atom of Met-35 oxidized to a sulfoxide (Met(O)Abeta) is toxic to neuronal cells, and this toxicity is attenuated by the metal chelator clioquinol and completely rescued by catalase implicating the same toxicity mechanism as reduced Abeta.

Studies on serotonergic markers in the human hippocampus: changes in subjects with bipolar disorder.

Background: Various studies suggest the hippocampus and serotonergic systems are important in the pathology of bipolar disorder (BD). We therefore measured hippocampal serotonergic markers in post-mortem tissue from BD and control subjects.

Methods: The density and affinity of [3H]citalopram binding to the serotonin transporter (SERT), as well as the density of the 5HT(2A), 5HT(1A), 5HT(1D) and 5HT(1F) receptors were measured.

Dextromethorphan alters gene expression in rat brain hippocampus and cortex.

Dextromethorphan is a widely used anti-tussive drug with non-competitive antagonistic effects on excitatory amino acid receptors of the N-methyl-D-aspartate (NMDA) type. This study examined the effect of daily dextromethorphan administration on gene expression in rat brain hippocampus and cortex regions using Rat 5K cDNA microarrays. Triplicate microarray assays were performed at each time point (1, 3 and 10 days), and results were confirmed using semi-quantitative RT-PCR on a subset of differentially expressed cDNA.

Cannabis-sensitive dopaminergic markers in postmortem central nervous system: changes in schizophrenia.

Background: This study investigated if changes in pre-synaptic markers on dopaminergic neurons (dopamine transporter [DAT], tyrosine hydroxylase [TH]) were present in the caudate from subjects with schizophrenia who had Delta(9)(-)tetrahydrocannabinol (THC) in their blood at autopsy. These changes were posited because animal studies show that treatment with THC decreases dopamine uptake and TH in the striatum.

Methods: Studies utilized caudate, obtained postmortem, from 14 schizophrenic and 14 control subjects.

The cortical serotonin2A receptor and the pathology of schizophrenia: a likely accomplice.

A large body of evidence shows that there is a change in the density of cortical serotonin2A receptors (5HT2AR) in post-mortem CNS from subjects with schizophrenia. Furthermore, some antipsychotic drugs have also been shown to cause a decrease in the density of 5HT2AR in the rat CNS. Thus, it appeared possible that changes in this receptor in human post-mortem CNS simply reflected an antipsychotic drug effect.

Neurotoxicity from glutathione depletion is dependent on extracellular trace copper.

Glutathione (GSH) is an important antioxidant, and its depletion in neurons has been implicated in several neurodegenerative disorders. Aberrant copper metabolism is also implicated in neurodegeneration and may result in the generation of toxic free radicals. However, little is known about the relationship between GSH depletion and copper homeostasis.

Decreased muscarinic1 receptors in the dorsolateral prefrontal cortex of subjects with schizophrenia.

To test the hypothesis that muscarinic receptors are involved in the pathology of schizophrenia, we measured muscarinic(1) (M1R) and muscarinic(4)(M4R) protein and mRNA as well as [(3)H]pirenzepine binding in Brodmann's areas (BA) 9 and 40 obtained postmortem from 20 schizophrenic and 20 age/sex-matched control subjects. There was a significant decrease in [(3)H]pirenzepine binding to BA 9 (mean +/- SEM: 151 +/- 15 vs 195 +/- 10 fmol mg(-1) ETE; P< 0.02), but not BA 40 (143 +/- 13 vs 166 +/- 11 fmol mg(-1) ETE), from subjects with schizophrenia.

Platelet alpha- and gamma-synucleins in Parkinson's disease and normal control subjects.

Alpha-synuclein (alphaSN) has been implicated in Parkinson's Disease (PD) and alphaSN is a major component of Lewy bodies (LBs). This study explored platelets as a model system for study of alphaSN metabolism and platelet alphaSN as a diagnostic marker for PD. We used Western blot analysis to characterize and compare platelet and brain alpha-, beta- and gammaSN; and to quantitate alphaSN levels in platelets from PD and age-matched controls.

Decreased density of [3H]TCP binding following antipsychotic drug withdrawal in rats.

Antipsychotic drugs have been reported to increase the expression of subunits of the NMDA receptor at the level of mRNA but it is not clear whether such effects are apparent at the level of the radioligand binding or receptor protein. Therefore, we examined the effect of treatment of, and withdrawal from, haloperidol, chlorpromazine, olanzapine or clozapine on the binding of [3H]N-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP ) to the open ion channel of the NMDA receptor in rat caudate-putamen, hippocampus and frontal cortex. [3H]TCP binding was not significantly different in the caudate-putamen, hippocampus and cortex after three months of treatment with any antipsychotic drug.

The heterogeneity of central benzodiazepine receptor subtypes in the human hippocampal formation, frontal cortex and cerebellum using [3H]flumazenil and zolpidem.

The ability of clonazepam and zolpidem to displace [3H]flumazenil binding was measured in the human hippocampal formation, frontal cortex (BA9) and the cerebellum using in situ radioligand binding and autoradiography. The use of high resolution phosphorimaging in all regions indicated the displacement of [3H]flumazenil by clonazepam was monophasic with K(i) values ranging from 2.73+/-0.

Decreased phorbol ester binding in the parahippocampal gyrus from subjects with schizophrenia is not associated with changes in protein kinase C.

Combining in situ radioligand binding with autoradiography, we previously identified a reduction of [(3)H]phorbol 12,13-dibutyrate binding in the parahippocampal gyrus from schizophrenic subjects. To determine whether these changes were due to decreases in the level of protein kinase C, we measured [(3)H]phorbol 12,13-dibutyrate binding, levels of the protein kinase C isoforms alpha, beta, delta, epsilon, gamma, eta and theta, as well as protein kinase C activity in crude particulate membranes from parahippocampal gyri of 15 schizophrenic and 15 control subjects. There was a significant decrease in the density (mean +/- SEM: 6.

High-resolution phosphor imaging: validation for use with human brain tissue sections to determine the affinity and density of radioligand binding.

This study investigated the suitability of high-resolution storage phosphor imaging for the quantitative analysis of radioligand binding to human brain tissue. Hence, the binding of [(3)H]mazindol to the dopamine transporter in caudate-putamen tissue homogenates or frozen tissue sections apposed to either autoradiographic film or phosphor imaging plates was measured. Estimates of binding affinity were similar for homogenate studies and phosphor imaging plates (Kd=6.

Understanding the pathology of schizophrenia: recent advances from the study of the molecular architecture of postmortem CNS tissue.

The use of central nervous system (CNS) tissue obtained postmortem has long underpinned efforts to understand the neurobiology of schizophrenia, but the ability to use such tissue in conjunction with a wide variety of methodologies has seen a renaissance of interest in this area of research. Recent findings have shown changes in markers in a number of neurotransmitter systems in the brains of subjects with schizophrenia which include the dopaminergic, serotonergic, cholinergic, glutamatergic, and GABAergic systems of the CNS. Many of these changes also appear to be regionally specific, and abnormalities in non-neurotransmitter specific pathways have been found in schizophrenia.

[(3)H]Flumazenil binding in the human hippocampal formation, frontal cortex and cerebellum detected by high-resolution phosphorimaging.

The pharmacological characterisation of the benzodiazepine binding site associated with the gamma-aminobutyric acid (GABA(A)) receptor in human brain has been demonstrated using in situ radioligand binding and autoradiography. The use of high-resolution phosphorimaging has allowed both the affinity (K(d)) and density (B(max)) of [(3)H]flumazenil binding to be measured within regions of the hippocampal formation as well as the cerebellum and frontal cortex. The Scatchard plots of data from all brain regions were linear with Hill coefficients close to unity consistent with the presence of a single binding site for [(3)H]flumazenil.

Studies on dopaminergic and GABAergic markers in striatum reveals a decrease in the dopamine transporter in schizophrenia.

Changes in the interaction between dopaminergic and GABAergic systems in the striatum have been suggested to be important in the pathology of schizophrenia. If that hypothesis is correct, these changes could produce inter-related changes in the dopaminergic and GABAergic systems in the striatum from schizophrenic subjects. To test this proposition we measured important markers on dopaminergic and GABAergic neurons in striatum obtained post-mortem from schizophrenic and non-schizophrenic subjects.

A change in the density of [(3)H]flumazenil, but not [(3)H]muscimol binding, in Brodmann's Area 9 from subjects with bipolar disorder.

Background: This study examines the hypothesis that there are changes in cortical serotonergic, GABAergic and glutamatergic systems in bipolar disorder and schizophrenia.

Methods: In situ radioligand binding and autoradiography were used to measure neurochemical markers in Brodmann's Area (BA) 9 from control subjects and subjects with bipolar disorder or schizophrenia (n=8 per group).

Results: Compared to tissue from schizophrenic (mean+/-S.

How reliable are reported plasma clozapine levels?

Objective: Many practitioners use plasma levels to determine the optimum dosage of clozapine. The aim of this study was to determine the intra- and interlaboratory accuracy in assaying samples of clozapine dissolved in human plasma.

Method: Three samples were sent to one laboratory to obtain an initial determination of accuracy (phase I).

Extended treatment with typical and atypical antipsychotic drugs differential effects on the densities of dopamine D2-like and GABAA receptors in rat striatum.

In situ radioligand binding and quantitative autoradiography have been used to measure the density of striatal D1-like, D2-like, and GABAA receptors in rats treated with haloperidol at 0.01 or 0.1 mg/kg/ day or chlorpromazine, olanzapine or clozapine at 0.

Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice.

Inhibition of neocortical beta-amyloid (Abeta) accumulation may be essential in an effective therapeutic intervention for Alzheimer's disease (AD). Cu and Zn are enriched in Abeta deposits in AD, which are solubilized by Cu/Zn-selective chelators in vitro. Here we report a 49% decrease in brain Abeta deposition (-375 microg/g wet weight, p = 0.

Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use.

A number of studies suggested that cannabis use can cause or exacerbate psychoses and may increase the risk of developing schizophrenia. These findings suggest that changes in the cannabinoid system of the brain may be involved in the pathology of schizophrenia. To determine whether changes in the cannabinoid system were present in the brains of subjects with schizophrenia, we used in situ radioligand binding and autoradiography to measure the binding of [3H]CP-55940 to the cannabinoid-1 receptor in the dorsolateral prefrontal cortex (Brodmann's area 9), caudate-putamen and areas of the temporal lobe from schizophrenic and control subjects, some of whom had ingested cannabis close to death.