Dopaminergic sensitization: implications for the pathogenesis of schizophrenia

1. Which transmitters are primarily or secondarily involved in the pathogenesis of schizophrenia has been extensively studied during the last years. This review concentrates on the two systems, that most constantly have been found dysfunctioning in patients; that are the dopaminergic and glutamatergic systems. 2. Numerous neuropathological defects have been found in schizophrenia, but it is as yet unknown which changes are causative and which reflect maladaptive reactions. 3. All findings, however, involve the cortico-striato-thalamo-cortical circuits, which are central for attention and information processing. 4. The article focuses on the consequence of transmitter dysfunction for perception and for the ability of the individual to adapt to a constantly changing environment. Both clinical and experimental studies point to a primary/early cortical defect involving the glutamatergic system, and to a later developed intermittent hyperactivity of the dopaminergic system superimposed on a basal hypodopaminergic state. 5. The authors have previously demonstrated, how it is possible to potentiate mesolimbic dopaminergic activity by intermittent electrical stimulations of the cells in the ventral tegmental area, and that influence on the central mesolimbic dopamine cells is essential for the strengthened neuroplastic response. A changed neuroplastic response to environmental stimulation due to dopaminergic sensitization can explain how an episodic, subcortical hyperactivity can act on a basic glutamatergic and dopaminergic hypofunction to produce psychotic symptoms. Based on our own and others clinical and experimental findings, the "filter" hypothesis for schizophrenia and the state-dependence of schizophrenic symptoms, the authors present a hypothesis for spontaneous mesolimbic dopaminergic sensitization and progressive evolution of psychosis.     

Hippocampal cell firing correlates of delayed-match-to-sample performance in the rat

Hippocampal CA1 and CA3 neurons were recorded in rats performing a delayed-match-to-sample (DMTS) task. Complex spike cells showed significant firing peaks following sample and match responses and during delivery of water reward. Individual cells were classified into 4 subtypes according to the presence or absence of firing in each of these 3 phases. There were significant differences in delay interval firing among the 4 subtypes, but firing during the delay did not predict the correct response: 34% of the cells showed a linear change in firing during the delay. Further analyses revealed significant lever position firing biases in approximately 70% of the cells tested irrespective of subtype. The complexity of firing correlates of the neurons recorded in this DMTS task suggests that the hippocampus divides specific aspects of the performance demands of the task across different cell subtypes, which together provide sufficient information to resolve the matching-to-sample problem on any given trial.     

Rabies virus quasispecies: implications for pathogenesis

Passage of the mouse-adapted rabies virus strain CVS-24 (where CVS is challenge virus standard) in BHK cells results in the rapid selection of a dominant variant designated CVS-B2c that differs genotypically and phenotypically from the dominant variant CVS-N2c present in mouse-brain- or neuroblastoma-cell-passaged CVS-24. The glycoprotein of CVS-B2c has 10 amino acid substitutions compared with that of CVS-N2c. Because CVS-B2c can be reproducibly selected in BHK cells, it is likely to be a conserved minor subpopulation of CVS-24. CVS-N2c is more neurotropic in vitro and in vivo than CVS-B2c, which replicates more readily in nonneuronal cells in vitro and in vivo. These characteristics appear to be relevant to the pathogenicity of the two variants. CVS-N2c is more pathogenic for adult mice than CVS-B2c. In contrast, CVS-B2c is more pathogenic for neonatal mice. These differences in pathogenicity are reflected in the selection pattern when mixtures of CVS-N2c and CVS-B2c were used to infect neonatal and adult mice. Although CVS-N2c was highly selected in adult mice, no selection for either variant was seen in neonates, suggesting that certain aspects of development, such as maturation of the nervous and immune systems, may contribute to the selection process. We speculate that the existence of different variants within a rabies virus strain may facilitate the virus in overcoming barriers to its spread, both within the host and between species.     

Hippocampal damage and schizophrenia: A critique of Mednick's theory.

Discusses S. A. Mednick's hypothesis that anoxia produced by pregnancy and birth complications causes hippocampal damage which in turn leads to schizophrenia in a predisposed individual. He further suggests that since the hippocampus exerts an inhibitory influence on reticular formation control of ACTH, a lesion in the hippocampus could cause oversecretion of ACTH. Contrary to Mednick's position, a survey of recent research findings showed: (a) Hippocampal control of ACTH is not inhibitory. Experimentally induced lesions of the hippocampus inhibit or facilitate ACTH release depending on the type of stress induced. (b) There are species differences in the type of behavioral deficits observed after a hippocampectomy. (c) The site of anatomical destruction due to anoxia will differ depending upon the species studied and the gestation level of the fetus exposed to anoxic conditions. Hippocampal damage is seldom found in the premature or full-term neonate primate. (39 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Apoptosis in restenosis versus stable-angina atherosclerosis: implications for the pathogenesis of restenosis

Decreases in programmed cell death (apoptosis) may contribute to restenotic hyperplasia by prolonging the life span of intimal cells. Apoptotic events were compared in restenotic versus primary lesions, by using atherectomy samples from 16 restenotic and 30 primary human peripheral and coronary lesions from patients presenting with stable angina. We used transmission electron microscopy to identify apoptosis, quantify its frequency, distinguish apoptosis from necrosis, and relate these events to cellular composition. Smooth muscle cell (SMC) density was higher in restenotic versus primary lesions (P<0.0001), whereas the number of macrophages was significantly reduced (P<0.01) and the number of lymphocytes was lower, but not significantly (P=0.06). As the main finding, restenotic lesions contained fewer apoptotic cells compared with primary lesions (3% versus 13%, P=0.002), whereas no differences were found for cellular necrosis. With regard to cell type, the lower frequency of apoptotic cells observed in restenotic tissue was attributable to both SMCs and macrophages. The key finding of less apoptosis in restenotic versus primary lesions was in agreement with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) analysis (2% versus 9%, P<0.001). For all lesions analyzed, significant inverse correlations were observed between the density of SMCs and the frequency of apoptotic cell death (r=-0.60, P<0.001) as well as the density of SMCs and that of macrophages (r=-0.74, P<0.001). No relationship was seen between the frequency of apoptosis and the density of macrophages. In conclusion, the data of the present study indicate that a low level of apoptosis may be an important mechanism leading to restenotic intimal lesion development after interventional procedures.     

Attempted suicide among Inuit youth: psychosocial correlates and implications for prevention

OBJECTIVE: To identify potential risk and protective factors associated with attempted suicide among Inuit youth, a population known to have a high rate of both attempted and completed suicide in recent years. METHOD: A secondary analysis of data on 203 Inuit youth (aged 15 to 24 years) from a random community survey conducted by Santé Québec in 1992. Factors previously identified in the literature and in clinical consultation and ethnographic research were tested with bivariate statistics and logistic regression models for each gender. RESULTS: At the bivariate level, positive correlates included substance use (solvents, cannabis, cocaine), recent alcohol abuse, evidence of a psychiatric problem, and a greater number of life events in the last year. Regular church attendance was negatively associated with attempted suicide. Multivariate analysis indicated that a psychiatric problem, recent alcohol abuse, and cocaine or crack use were the strongest correlates of attempted suicide for females, while solvent use and number of recent life events were the strongest correlates for males. CONCLUSIONS: Suicide prevention programs can be targeted at youth who are using substances, particularly solvents, cocaine, and alcohol, have psychiatric illness, and have experienced recent negative life events. Involvement in church or other community activities may reduce the risk for suicide. Consideration of gender differences may allow more precise identification of those at risk for attempted suicide.     

Autonomic correlates of chronic schizophrenia: A reaction time paradigm.

Assessed basal, tonic, and 2 phasic measures of heart rate and skin conductance among 16 drug-free, chronic, process, nonparanoid schizophrenics, and 2 groups of control Ss (hospital staff and prison inmates). Of particular interest were changes in autonomic activity that attended manipulation of "go" signal intensity within a reaction time paradigm. Among control Ss, increased signal intensity produced increases in tonic levels and amplitude of anticipatory responding. Among schizophrenics, however, the reverse occurred: Increased signal intensity resulted in decreased tonic levels and inhibition of anticipatory responding. Schizophrenic responses occurred in the absence of basal level differences between groups. Results are interpreted as indicating the presence of a learned anticipatory set that serves to reduce the impact of stimulus intensity. This inhibitory set would also appear to reduce receptivity to the cue component of stimuli. (16 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Vesicular transport: implications for cell polarity

In polarized cells intracellular sorting of plasma membrane proteins occurs to a large extent at the trans-Golgi network, giving rise to vesicles destined for distinct plasma membrane domains. This review discusses the several pathways, both direct and indirect, which lead to protein incorporation into the correct cell surface, as well as the mechanisms involved. Proteins contain signals which direct their incorporation into the distinct vesicles destined for plasma membrane microdomains. Specific coat proteins are involved in vesicle assembly and are likely to play a role in the generation of discrete vesicle populations. Molecules involved in vesicle docking and fusion may also add specificity to the targeting process.     

Activation of CD8+ T lymphocytes through the T cell receptor turns on CD4 gene expression: implications for HIV pathogenesis

T cell activation through the T cell receptor is necessary to achieve a specific and effective immune response. We report here that stimulation of CD8+ T cells through the T cell receptor complex leads to de novo expression of the CD4 antigen on the cell surface that results in susceptibility of CD8+ T cells to HIV infection. In addition, activation of peripheral blood mononuclear cells from HIV-infected individuals results in the appearance of double-positive CD4+/CD8+ T cells, which become infected by endogenous HIV. HIV DNA sequences could be detected in uncultured and sorted mature CD3+CD8+ T cells from HIV+ individuals. These results suggest a new mechanism by which HIV could attack the immune system and may help to explain the CD8+ T cell defects in AIDS patients.     

Brain potential correlates of number errors in the Turkish language

Event-related potentials (ERPs) were recorded from 16 native speakers of Turkish while they watched Turkish sentences flashed upon the screen of a videomonitor. The sentences were three words long and contained a verb at the terminal position that was manipulated (1) to have either the correct or the incorrect number with regard to the subject of the sentence, and (2) to be semantically appropriate, inappropriate or to be a pseudoverb. The ERPs from 19 scalp channels revealed a more positive waveform at the left-fronto-temporal site with an onset latency of about 200 ms for the verbs having the wrong number regardless of the semantic appropriateness of the word, while at right fronto-temporal sites a more negative waveform was observed for plural words only. This number incongruency ERP-effect in Turkish is clearly at odds with findings from other languages.     

Telomerase and the aging cell: implications for human health

Recent research has shown that inserting a gene for the protein component of telomerase into senescent human cells reextends their telomeres to lengths typical of young cells, and the cells then display all the other identifiable characteristics of young, healthy cells. This advance not only suggests that telomeres are the central timing mechanism for cellular aging, but also demonstrates that such a mechanism can be reset, extending the replicative life span of such cells and resulting in markers of gene expression typical of "younger" (ie, early passage) cells without the hallmarks of malignant transformation. It is now possible to explore the fundamental cellular mechanisms underlying human aging, clarifying the role played by replicative senescence. By implication, we may soon be able to determine the extent to which the major causes of death and disability in aging populations in developed countries-cancer, atherosclerosis, osteoarthritis, macular degeneration, and Alzheimer dementia--are attributable to such fundamental mechanisms. If they are amenable to prevention or treatment by alteration of cellular senescence, the clinical implications have few historic precedents.     

Differential distribution of ciliated epithelial cells in the trachea of hamsters: implications for studies of pathogenesis

The morphology of the inner aspect of the adult hamster trachea was examined by scanning electron microscopy. Relatively large patches of unciliated cells were observed in the epithelial layer. The patches, which covered several hundreds to thousands of square microns, were most conspicuous on the ventral surface of the trachea, especially in the middle third. The frequency of these areas of unciliated cells, both isolated and in patches, was much greater in hamsters than in mice, rats, or cats. Greatest ciliation in the hamster trachea was observed over the strip of trachealis muscle between the open ends of the cartilaginous rings. Areas with the heaviest ciliation also had the greatest activity of cellular metabolism, as measured by the tetrazolium reduction assay. The attachment of tritium-labeled cells of Mycoplasma pneumoniae was inversely correlated with extensive ciliation, since the greatest numbers of counts were found on the middle third and ventral regions of the tracheal surface. The results of this study suggest that the regional differences in ciliation of respiratory epithelium in hamsters may influence studies of pathogenesis and isolation of M. pneumoniae and that these differences should therefore be considered and controlled in the experimental design.     

Automimmune response to dopamine-receptor as a possible mechanism in the pathogenesis of Parkinson's disease and schizophrenia

Clinical and neuropharmacological evidence indicates the involvement of dopaminergic mechanisms in Parkinson's disease and schizophrenia, as well as in iatrogenic Parkinsonism and drug-induced schizophrenia-like syndrome. The evidence hitherto presented stresses the existence of a reversed relationship between Parkinson's disease and schizophrenia and implicates the possibility that dysfunction of dopamine-receptors may be a central phenomenon in both diseases. In view of the recent demonstration of two separate dopamine-receptors, it is postulated that a striatal receptor blockade may cause Parkinson's disease, whereas a limbic receptor blockade may result in schizophrenia. The recent discovery that several autoimmune diseases, such as myasthenia gravis, are the result of an immunopharmacological block at receptor sites, together with several observations of immunological disorders in Parkinson's disease and schizophrenia, suggests the possibility that certain types of Parkinson's disease and schizophrenia might be the consequence of an autoimmune blockade of striatal or limbic dopamine-receptors, respectively.     

A pivotal role for glutamate in the pathogenesis of schizophrenia, and its cognitive dysfunction

PURPOSE: To compare the outcome for patients with squamous cell carcinoma of cervical lymph nodes metastatic from an unknown primary site who were irradiated to both sides of the neck and potential mucosal sites with opposed photon beams, and for those irradiated to the ipsilateral side of the neck alone with an electron beam. METHODS AND MATERIALS: Fifty-two patients with squamous cell carcinoma metastatic to cervical lymph nodes from an unknown primary site were irradiated by two different methods. Thirty-six were irradiated with a bilateral technique (BT), i.e., to both sides of the neck, including the naso-oro-hypopharyngeal mucosa, and 16 were irradiated with an electron beam (EB) to the ipsilateral side of the neck alone. Twenty patients of the BT group and 11 of the EB group had cervical lymph node dissections, and the remaining 21 patients had lymph node biopsies, prior to radiotherapy. RESULTS: Tumor control in the ipsilateral side of the neck did not differ for either radiation technique, but was significantly higher after lymph node dissection than after biopsy (90 vs. 48%; p = 0.0004). Control of subclinical metastases in the contralateral cervical lymph nodes was higher for patients irradiated with BT than for patients irradiated with EB (86 vs. 56%; p = 0.03). The occult primary was later discovered in 8% of the patients in the BT group and 44% of the EB group (p = 0.0005). The disease-free survival rate at 5 years for patients who had lymph node dissection prior to irradiation was 61%, and was 37% for those who had biopsy (p = 0.05). Only 20% of patients who subsequently developed an occult primary were salvaged and survived for 5 years after salvage treatment. CONCLUSION: Bilateral neck and mucosal irradiation is superior to ipsilateral neck irradiation in preventing contralateral cervical lymph node metastases and the subsequent appearance of an occult primary cancer. Both techniques combined with cervical lymph node dissection were equally effective in controlling the ipsilateral neck disease.     

Hippocampal N-acetyl aspartate in unaffected siblings of patients with schizophrenia: a possible intermediate neurobiological phenotype

BACKGROUND: Shared neurobiological characteristics of patients with schizophrenia and their siblings may represent "intermediate phenotypes" that may more closely reflect the genetic susceptibility underlying this illness. We sought evidence of such phenotypes using magnetic resonance spectroscopy based on previously described regional abnormalities in levels of the neuronal marker N-acetyl-aspartate (NAA) in the hippocampal area and dorsolateral prefrontal cortex of patients with schizophrenia. METHODS: We studied 47 schizophrenics, 60 unaffected siblings, and 66 healthy control subjects with long echo time multislice proton magnetic resonance spectroscopic imaging, primarily measuring NAA, creatine plus phosphocreatine (CRE), and choline-containing compounds. RESULTS: Both patients and their unaffected siblings had significant reductions in hippocampal area NAA/CRE as compared with control subjects. As exploratory analyses, estimates of heritability were performed. Although quantitative correlation of hippocampal NAA between patients and sibs was low (likely reflecting measurement noise), qualitatively defined "low hippocampal NAA/CRE phenotypes" yielded relative risk estimates (lambda s) of between 3.8 and 8.8, suggesting this characteristic is heritable. CONCLUSIONS: Our finding adds to the evidence that hippocampal abnormalities are associated with schizophrenia and may represent a novel biological phenotype for genetic studies of schizophrenia.     

Heat-shock proteins and molecular chaperones: implications for pathogenesis, diagnostics, and therapeutics

Cells react to physical (e.g., heat) or chemical (e.g., anoxia, low pH) stressors, mounting a stress (heat-shock) response. Most genes are turned down or off, while a few are activated. The latter encode the stress or heat-shock proteins (Hsps), whose levels increase in stressed cells. Various Hsps are molecular chaperones. These, and other molecular chaperones that are not Hsps, help the other cellular proteins to achieve their native state (correct folding or functional conformation), reach their final destination (e.g., the endoplasmic reticulum or the mitochondria), resist denaturing by stressors, and regain the native state after partial denaturation. Thus the Hsps and molecular chaperones occupy the stage's center whenever and wherever there is cellular and tissue injury caused by local or systemic stressors via protein damage. This feature, their participation in protein folding and transport, and their evolutionary conservation within the three phylogenetic domains, strongly suggest a vital role for Hsps and molecular chaperones. Their importance in pathogenesis, and as diagnostic markers and prognostic indicators, is beginning to be appreciated. The role of Hsps and molecular chaperones in cell recovery from injury by a variety of noxae of clinical and surgical relevance is also being assessed. Consequently, the potential of these molecules (and corresponding genes) as targets for treatment or as therapeutic tools is emerging and is being explored. Stroke, myocardial infarction, inflammatory syndromes, infectious and parasitic diseases, autoimmune disorders, cancer, and aging are but some examples of conditions in which Hsps and molecular chaperones are being scrutinized. The era of Hsp and molecular chaperone pathology has dawned. It is likely that genetic and acquired defects of Hsp and molecular chaperone structure and function will be identified, and will play a primary, or auxiliary but determinant, role in disease.     

The genotype of the human cancer cell: implications for risk analysis

An extremely large database describes genotypes associated with the human cancer phenotype and genotypes of human populations with genetic predisposition to cancer. Aspects of this database are examined from the perspective of risk analysis, and the following conclusions and hypotheses are proposed: (1) The genotypes of human cancer cells are characterized by multiple mutated genes. Each type of cancer is characterized by a set of mutated genes, a subset from a total of more than 80 genes, that varies between tissue types and between different tumors from the same tissue. No single cancer-associated gene nor carcinogenic pathway appears suitable as an overall indicator whose induction serves as a quantitative marker for risk analysis. (2) Genetic defects that predispose human populations to cancer are numerous and diverse, and provide a model for associating cancer rates with induced genetic changes. As these syndromes contribute significantly to the overall cancer rate, risk analysis should include an estimation of the effect of putative carcinogens on individuals with genetic predisposition. (3) Gene activation and inactivation events are observed in the cancer genotype at different frequencies, and the potency of carcinogens to induce these events varies significantly. There is a paradox between the observed frequency for induction of single mutational events in test systems and the frequency of multiple events in a single cancer cell, suggesting events are not independent. Quantitative prediction of cancer risk will depend on identifying rate-limiting events in carcinogenesis. Hyperproliferation and hypermutation may be such events. (4) Four sets of data suggest that hypermutation may be an important carcinogenic process. Current mechanisms of risk analysis do not properly evaluate the potency of putative carcinogens to induce the hypermutable state or to increase mutation in hypermutable cells. (5) High-dose exposure to carcinogens in model systems changes patterns of gene expression and may induce protective effects through delay in cell progression and other processes that affect mutagenesis and toxicity. Paradigms in risk analysis that require extrapolation over wide ranges of exposure levels may be flawed mechanistically and may underestimate carcinogenic effects of test agents at environmental levels. Characteristics of the human cancer genotype suggest that approaches to risk analysis must be broadened to consider the multiplicity of carcinogenic pathways and the relative roles of hyperproliferation and hypermutation. Further, estimation of risk to general human populations must consider effects on hypersusceptible individuals. The extrapolation of effects over wide exposure levels is an imprecise process.