Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In most psychiatric disorders, stress is the major nongenomic factor that contributes to the expression or exacerbation of acute symptoms, recurrence or relapse after a period of remission, and treatment outcome. Delineation of mechanisms by which stress contributes to these processes is fundamental to understanding the disease process and for improving outcome. In this article, evidence is reviewed to indicate that many central aspects of stress response, including activation of the hypothalmic-pituitary-adrenal (HPA) axis and dopamine neurotransmission, are modulated, and in some cases mediated, by glutamate neurotransmission in the prefrontal cortex (PFC). It is suggested that activation of glutamatergic neurotransmission in the PFC presents a common mechanism by which stress influences normal and abnormal processes that sustain affect and cognition. Although monoamines, in particular dopamine, have been considered the major culprits in the adverse effects of stress in disorders such as addiction and schizophrenia, it is likely that in a vulnerable brain with an underlying PFC pathophysiology, abnormal stress-activated monoaminergic neurotransmission is secondary to anomalies in cortical glutamate neurotransmission. Thus, understanding the contribution of glutamate-mediated processes to stress response through the use of experimental models that involve disrupted PFC function can provide insights to the fundamental pathophysiology of stress-sensitive psychiatric disorders and lead to novel strategies for treatment and prevention.
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PMID:Stress activation of glutamate neurotransmission in the prefrontal cortex: implications for dopamine-associated psychiatric disorders. 1200 51

The nine membrane-bound isoforms of the enzyme adenylate cyclase (EC 4.6.1.1) are highly regulated by neurotransmitters and drugs acting through G protein-coupled receptors to modulate intracellular cAMP levels. In general, acute activation of Galpha(s)-coupled receptors stimulates cAMP accumulation, whereas acute activation of Galpha(i/o)-coupled receptors typically inhibits cAMP accumulation. It is also well established that persistent activation of G-protein coupled receptors will alter subsequent drug-modulated cAMP accumulation. These alterations are thought to represent cellular adaptive responses following prolonged receptor activation. One phenomenon commonly observed, heterologous sensitization of adenylate cyclase, is characterized by an enhanced responsiveness to drug-stimulated cAMP accumulation following persistent activation of Galpha(i/o)-coupled receptors. Heterologous sensitization of adenylate cyclase was originally proposed to explain tolerance and withdrawal following chronic opiate administration and may be a mechanism by which cells adapt to prolonged activation of inhibitory receptors. Such an adaptive mechanism has been suggested to play a role in the processes of addiction to and withdrawal from many drugs of abuse and in psychiatric disorders including schizophrenia and depression. Although the precise mechanisms remain unknown, research over the last decade has led to advances toward understanding the molecular events associated with heterologous sensitization of recombinant and endogenous adenylate cyclases in cellular models. These events include the pertussis toxin-sensitive events that are associated with the development of heterologous sensitization and the more recently identified Galpha(s)-dependent events that are involved in the expression of heterologous sensitization.
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PMID:Molecular mechanisms for heterologous sensitization of adenylate cyclase. 1206 93

Sydnocarb [(phenylisopropyl)N-phenylcarbamoylsydnonimine; SYD] was introduced to clinical practice in Russia as a psychostimulant drug used for the treatment of asthenia and apathy, which accompany schizophrenia and manic depression. It has been described as a psychostimulant with addiction liability and toxicity less than amphetamine (AMPH). The precise cellular mechanisms by which sydnocarb elicits its psychostimulant effect are still unclear. At present its neurochemical and neurotoxic effects are compared to those of AMPH in the striatum, the main input structure of the basal ganglia. The expression of c-fos protein in striatal neurons was much more increased after a single injection of D-AMPH (5 mg/kg) than after an equimolar concentration of SYD (23.8 mg/kg) in both the anterior and the posterior part of the striatum. Using in situ hybridization on striatal slices, we observed that AMPH increased the striatal levels of preprodynorphin (PPDYN) mRNAs in both parts of the striatum, while SYD did not affect basal levels of PPDYN mRNAs. Furthermore, AMPH and SYD increased striatal preprotachykinin (PPT-A) and preproenkephalin (PPE) mRNA levels. The effects of AMPH and SYD on PPT-A-mRNA levels were similar. A differential effect of AMPH and SYD was observed only on the PPE-mRNA levels measured in the anterior striatum where SYD increased these levels more than AMPH. The acute neurotoxicity of these two psychostimulants was analyzed by measuring their effects on the parameters of oxidative stress, such as nitric oxide (NO) generation, as well as specific indices of lipid peroxidation (i.e., thiobarbituric acid reactive substances; TBARS), while, on the other hand, the alpha-tocopherol level was taken as an index of antioxidant defense processes. Measuring generation of NO directly by electron paramagnetic resonance, it was observed that AMPH shows a more pronounced increase in comparison to SYD, in the striatum and in cortex. TBARS levels in the striatum and cortex were significantly less enhanced than AMPH after a single injection of SYD. Similarly, the alpha-tocopherol level was decreased only by AMPH in the striatum, and neither AMPH nor SYD had any effect in the cortex. Results show that a single injection of a high dose of AMPH is able to induce several neurotoxic effects. The study also demonstrates that SYD has mild neurochemical effects as well as fewer neurotoxic properties than AMPH.
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PMID:Neurochemical changes and neurotoxic effects of an acute treatment with sydnocarb, a novel psychostimulant: comparison with D-amphetamine. 1210 94

Since its development, microarray technique has revolutionized almost all fields of biomedical research by enabling high-throughput gene expression profiling. Using cDNA microarrays, thousands of genes from various organisms have been examined with respect to differentiation/development, disease diagnosis, and drug discovery Nevertheless, research on nicotine using cDNA microarrays has been rather limited. Therefore, it is our intention in this article to report the findings of our cDNA microarray study on nicotine. We first present an overview of the microarray technology, particularly focusing on the factors related to microarray design and analysis. Second, we provide a detailed description of several newly identified biological pathways in our laboratory, such as phosphatidylinositol signaling and calcium homeostasis, which are involved in response to chronic nicotine administration. Additionally, we illustrate how comparisons between microarray studies help identify candidate genes that potentially may explain the observed inverse association between smoking and schizophrenia. Lastly, given the early stage of microarray research on nicotine, we elaborate on the need for an efficient analysis of genetic networks to further enhance our understanding of the mechanisms involved in nicotine abuse and addiction.
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PMID:Microarray technology and its application on nicotine research. 1210 75

We evaluated literature that addresses the notion that flexible smoking treatment approaches are warranted for smokers with a diagnosis of schizophrenia. Understanding the biological and psychological mechanisms that increase the likelihood of smoking and decrease the motivation to quit for these individuals is addressed within the framework of a neurobiological model. We provide a brief overview of the limited smoking cessation treatment literature for patients with schizophrenia and compare abstinence-focused versus reduction-focused treatment modalities. The potential utility of the reduction-focused approach to tobacco treatment for these smokers is evaluated. Suggestions for future research to address the utility and efficacy of reduction-focused interventions for smokers with schizophrenia are put forth. We conclude with a consideration of the implications for the current understanding of smoking treatment among patients with co-morbid psychiatric diagnoses.
Addiction 2002 Jul
PMID:Would smokers with schizophrenia benefit from a more flexible approach to smoking treatment? 1213 13

Among the elements of comorbidity found in schizophrenia, it is addiction and violence that figure most among those that preoccupy the entourage of family and cares of patients. These problems can worsen the prognosis of schizophrenia, notably because they further hinder the already complex provision of care and social support, but also because they provoke a cascade of complications and disruptions. On top of these in comorbid manifestations exist fears, preconceived ideas and shady zones. The authors of this article propose a review of the recent literature, on the incidence and nature of these problems, and on the pathways currently being explored as to their origins.
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PMID:[Schizophrenia and comorbidity: addictions and violence]. 1214 2

We present a clinical case of a psychotic drug abuser. The diagnostic hypothesis was paranoid schizophrenia. This case clearly demonstrates the diagnostic duel between schizophrenia and heroine addiction. Based on this case, we hypothesize that use of drugs in such a patient fulfils an appeasing function rather than pathological burial. It would be interesting to determine the specificity of how this type of patient uses drugs, beyond the apparent double incidence of two diagnoses, in the mode of decompensation and chronic progression of the disease, which would be particularly useful for developing a treatment strategy.
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PMID:[Is double diagnosis appropriate? A case of schizophrenia and heroine addiction]. 1221 82

Alteration in the isoprenoid metabolites--digoxin, ubiquinone, and dolichol--have been reported in neuronal degeneration (Parkinson's disease), oncogenesis (central nervous system glioma), functional neuropsychiatric disorders (schizophrenia and epilepsy), and immune-mediated disorders (multiple sclerosis). The coexistence of these disorders has been documented in literature and a central dysfunction related to digoxin and the isoprenoid pathway may underlie all these disorders. A family with a high prevalence of Parkinson's disease, schizophrenia, neoplasms, syndrome X, rheumatoid arthritis, and epilepsy has been described. The psychological behavioral patterns of the family were: creativity and high IQ, hypersexual behavior, reduced appetite and eating behavior, insomnia and reduced sleep patterns, increased tendency for spirituality, increased tendency for addiction, less bonding and affectionate behavior, and left handedness/right hemispheric dominance. Digoxin, an endogenous Na(+)-K+ ATPase inhibitor secreted by the hypothalamus, was found to be elevated and red blood cell (RBC) membrane Na(+)-K+ ATPase activity was found to be reduced in all the disorders and in the indexed family studied. Hypothalamic digoxin can modulate conscious perception and its dysfunction may lead to schizophrenia. Digoxin can also preferentially upregulate tryptophan transport over tyrosine, resulting in increased levels of depolarizng tryptophan catabolites, serotonin, quinolinic acid, strychnine, and nicotine, and decreased levels of hyperpolarizing tyrosine catabolites, dopamine, noradrenaline, and morphine, contributing to membrane Na(+)-K+ ATPase inhibition in all the above disorders and the indexed family. Digoxin-induced membrane Na(+)-K+ ATPase inhibition can result in increased intracellular Ca2+ and reduced Mg2+ levels, leading on to glutamate excitotoxicity, oncogene activation, and immune activation. Digoxin-induced altered Ca2+/Mg2+ ratios, reduced ubiquinone, and increased dolichol can affect glycoconjugate metabolism, membrane formation and structure, and mitochondrial function, leading to the diverse disorders described above, including those in the indexed family. The isoprenoid pathway and neurotransmitter patterns were compared in right-handed/LH dominant and left-handed/RH dominant individuals. The left-handed/RH dominant individuals compared to right-handed/LH dominant individuals had elevated hydroxymethylglutarylcoenzyme A reductase activity, with increased serum digoxin and dolichol levels. The serum ubiquinone, serum Mg2+ and RBC Na(+)-K+ ATPase activity were reduced in left-handed/RH dominant individuals. The left-handed/RH dominant individuals compared to right-handed/LH dominant individuals had elevated levels of serum tryptophan, quinolinic acid, serotonin, nicotine, and strychnine. The levels of tyrosine, dopamine, noradrenaline, and morphine were low in left-handed/RH dominant compared to right-handed/LH dominant individuals. The hyperdigoxinemic state indicates right hemispheric dominance. Hypothalamic digoxin can thus function as the master conductor of the neuroimmunoendocrine orchestra and coordinate the functions of various cellular organelles.
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PMID:Central role of hypothalamic digoxin in conscious perception, neuroimmunoendocrine integration, and coordination of cellular function: relation to hemispheric dominance. 1232 12

The similarity of mode of action, behavior, and gene response between Drosophila melanogaster and mammalian systems, combined with the power of genetics, have recently made the fly an attractive system to study underlying mechanisms of drug abuse, addiction, and mental disorders. The present studies define the behavioral and molecular effects of the powerful hallucinogen lysergic acid diethylamide in Drosophila. Pharmacological activation of serotonin receptors in the fly by lysergic acid diethylamide induces behaviors not unlike those observed in mammalian systems. These include alterations in visual processing abilities, reduced locomotor activity, and altered gene expression within the brain. Many of these effects are due to activation of the same serotonin receptor subtypes that are thought to be the primary mediators of hallucinogenic drug effects in humans as well as the acute symptoms of schizophrenia.We suggest that Drosophila can be used as a genetically tractable model system to define the molecular events leading from serotonin receptor activation to behavior, possibly revealing new targets for hallucinogenic agents and for the treatment of neuropsychiatric disorders such as schizophrenia.
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PMID:Hallucinogens and Drosophila: linking serotonin receptor activation to behavior. 1243 34

A family with a high prevalence of Parkinson's disease, schizophrenia, neoplasms, syndrome-X, rheumatoid arthritis and epilepsy has been described. The psychological behavioural patterns of the family were as follows--creativity and high IQ, hypersexual behaviour, reduced appetite and eating behaviour, insomnia and reduced sleep patterns, increased tendency for spirituality, increased tendency for addiction, less of bonding and affectionate behaviour and left handedness. Digoxin, an endogenous Na(+)-K(+) ATPase inhibitor secreted by the hypothalamus, was found to be elevated and RBC membrane Na(+)-K(+) ATPase activity was found to be reduced in all the disorders and in the indexed family studied. Hypothalamic digoxin can modulate conscious perception and its dysfunction may lead to schizophrenia. Digoxin can also preferentially upregulate tryptophan transport over tyrosine resulting in increased levels of depolarising tryptophan catabolites - serotonin, quinolinic acid, strychnine and nicotine and decreased levels of hyperpolarising tyrosine catabolites dopamine, noradrenaline and morphine contributing to membrane Na(+)-K(+) ATPase inhibition in all the above disorders and the indexed family. Digoxin induced membrane Na(+)-K(+) ATPase inhibition can result in increased intracellular Ca(2+) and reduced Mg(++) levels leading to glutamate excitotoxicity, oncogene activation and immune activation. Digoxin induced altered Ca(++)/Mg(++) ratios, reduced ubiquinone and increased dolichol can affect glycoconjugate metabolism, membrane formation and structure and mitochondrial function leading to the diverse disorders described above including those in the indexed family. The isoprenoid pathway and neurotransmitter patterns were compared in right-handed/left hemispheric dominant and left-handed/right hemispheric dominant individuals. The biochemical patterns in the indexed family and the diverse disorders studied correlated with those obtained in right hemispheric dominance. The hyperdigoxinemic state indicates right hemispheric dominance. Hypothalamic digoxin can thus function as the master conductor of the neuroimmunoendocrine orchestra and co-ordinate the functions of various cellular organelles.
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PMID:Hypothalamic digoxin--central role in conscious perception, neuroimmunoendocrine integration and coordination of cellular function--relation to hemispheric dominance. 1260 43


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