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)

Iloperidone is a novel psychotropic compound currently undergoing Phase III trials. Its affinity for human dopamine and 5-HT(2A) and 5-HT(2C) receptors has been reported previously. This report presents the affinity of iloperidone for a largely extended number of human neurotransmitter receptors. In a few instances human receptors were not available and receptor studies were performed on tissues from laboratory animals. The present data, supplemented with those of, indicate that iloperidone displays high affinity (K(I) < 10 nM) for norepinephrine alpha(1)-adrenoceptors, dopamine D(3) and serotonin 5-HT(2A) receptors. Intermediate affinity (10-100 nM) was found for norepinephrine alpha(2C)-adrenoceptors, dopamine D(2A) and D(4) receptors and serotonin 5-HT(1A), 5-HT(1B), 5-HT(2C) and 5-HT(6) receptors. The affinity for all other receptors was below 100 nM, including norepinephrine alpha(2A), alpha(2B), beta(1), and beta(2), muscarine M(1)-M(5), histamine H(1), dopamine D(1) and D(5), CCK(A) and CCK(B), 5-HT(7), dopamine and norepinephrine transporters. Thus, iloperidone targets a selective set of dopamine, norepinephrine and serotonin receptor subtypes. The affinity for this particular set of receptors indicates that iloperidone has the potential to be a broad spectrum antipsychotic, with efficacy against positive, negative, depressive and cognitive symptoms of schizophrenia, and a low propensity to induce side effects.
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PMID:Extended radioligand binding profile of iloperidone: a broad spectrum dopamine/serotonin/norepinephrine receptor antagonist for the management of psychotic disorders. 1175 Jan 83

Ziprasidone is a new antipsychotic with combined dopamine and serotonin receptor antagonist activity. The initial evidence suggests an effective dosage range of 80-160 mg/day. Clinical trials suggest that the drug is an effective antipsychotic in schizophrenia and schizoaffective disorder with a beneficial effect on negative symptoms and symptoms of depression. The main adverse effects appear to be somnolence (14%) and nausea (10%). Ziprasidone has relatively fewer side-effects and yet has at least equivalent efficacy for florid 'positive' symptoms compared with conventional antipsychotics. The additional serotonergic actions deliver further efficacy against 'negative' and affective symptoms of schizophrenia. Reduced effects on cognitive abilities compared to conventional antipsychotics make ziprasidone more attractive still. Barring any unforeseen complications, it appears to a most valuable addition to the antipsychotic agents.
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PMID:Focus on ziprasidone. 1175 85

Dorsolateral prefrontal cortex has an essential role in the cognitive process of working memory, dysfunction of which is considered to be a core deficit in schizophrenia. Although this cortical region is densely innervated with 5-HT2A receptors to which atypical antipsychotic drugs bind with high affinity, little is known of the influence of this serotonin receptor subtype on prefrontal function. We addressed this issue by examining the effects of iontophoresis of selective receptor ligands on prefrontal neurons possessing spatially tuned delay activity, or "memory fields," in monkeys performing a delayed-response task. Memory fields of putative pyramidal cells were attenuated by iontophoresis of 5-HT2A antagonists, which primarily produced a reduction in delay activity for preferred target locations. Conversely, 5-HT2A stimulation by alpha-methyl-5-HT or 5-HT itself, accentuated the spatial tuning of these neurons by producing a modest increase in activity for preferred target locations and/or a reduction in activity for nonpreferred locations. The agonist effects could be reversed by the selective antagonist MDL100,907, and were dose-dependent, such that high levels attenuated spatial tuning by profoundly reducing delay activity. A role for feedforward inhibitory circuitry in these effects was supported by the finding that 5-HT2A blockade also attenuated the memory fields of putative interneurons. We conclude that prefrontal 5-HT2A receptors have a hitherto unrecognized role in the cognitive function of working memory, which involves actions at both excitatory and inhibitory elements within local circuitry.
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PMID:The physiological role of 5-HT2A receptors in working memory. 1192 49

Hallucinogenic drugs such as lysergic acid diethylamide (LSD) have profound effects on humans including hallucinations and detachment from reality. These remarkable behavioral effects have many similarities to the debilitating symptoms of neuropsychiatric disorders such as schizophrenia. The effects of hallucinogens are thought to be mediated by serotonin receptor activation; however, how these drugs elicit the unusual behavioral effects remains largely a mystery, despite much research. We have undertaken the first comprehensive analysis of gene expression influenced by acute LSD administration in the mammalian brain. These studies represent a novel approach to elucidate the mechanism of action of this class of drugs. We have identified a number of genes that are predicted to be involved in the processes of synaptic plasticity, glutamatergic signaling and cytoskeletal architecture. Understanding these molecular events will lead to new insights into the etiology of disorders whose behavioral symptoms resemble the temporary effects of hallucinogenic drugs, and also may ultimately result in new therapies.
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PMID:A single dose of lysergic acid diethylamide influences gene expression patterns within the mammalian brain. 1192 88

Salvia divinorum, whose main active ingredient is the neoclerodane diterpene Salvinorin A, is a hallucinogenic plant in the mint family that has been used in traditional spiritual practices for its psychoactive properties by the Mazatecs of Oaxaca, Mexico. More recently, S. divinorum extracts and Salvinorin A have become more widely used in the U.S. as legal hallucinogens. We discovered that Salvinorin A potently and selectively inhibited (3)H-bremazocine binding to cloned kappa opioid receptors. Salvinorin A had no significant activity against a battery of 50 receptors, transporters, and ion channels and showed a distinctive profile compared with the prototypic hallucinogen lysergic acid diethylamide. Functional studies demonstrated that Salvinorin A is a potent kappa opioid agonist at cloned kappa opioid receptors expressed in human embryonic kidney-293 cells and at native kappa opioid receptors expressed in guinea pig brain. Importantly, Salvinorin A had no actions at the 5-HT(2A) serotonin receptor, the principal molecular target responsible for the actions of classical hallucinogens. Salvinorin A thus represents, to our knowledge, the first naturally occurring nonnitrogenous opioid-receptor subtype-selective agonist. Because Salvinorin A is a psychotomimetic selective for kappa opioid receptors, kappa opioid-selective antagonists may represent novel psychotherapeutic compounds for diseases manifested by perceptual distortions (e.g., schizophrenia, dementia, and bipolar disorders). Additionally, these results suggest that kappa opioid receptors play a prominent role in the modulation of human perception.
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PMID:Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. 1219 85

Ziprasidone is a new antipsychotic with combined dopamine and serotonin receptor antagonist activity. The initial evidence suggests an effective dosage range of 80-160 mg/day. Clinical trials suggest that the drug is an effective antipsychotic in schizophrenia and schizo-affective disorder with a beneficial effect on negative symptoms and symptoms of depression. The main adverse effects appear to be somnolence (14%) and nausea (10%). Ziprasidone has relatively fewer side effects and yet has at least equivalent efficacy for florid 'positive' symptoms compared to conventional anti psychotics. The additional serotonergic actions deliver further efficacy against 'negative' and affective symptoms of schizophrenia. Reduced effects on cognitive abilities compared to conventional anti psychotics make Ziprasidone more attractive.
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PMID:Brief report on Ziprasidone. 1239 87

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

To study the effect of the serotonergic brain system on verbal fluency (i.e., the ability to rapidly extract necessary words from the vocabulary), the T102C polymorphism of the serotonin receptor type 2A (5-HTR2A) gene was tested for association with verbal fluency in 108 patients with schizophrenia or schizotypic disorders and 97 mentally healthy individuals. A significant association was observed only in male schizophrenics (N = 67), with homozygotes A2A2 having lower verbal fluency. The results did not support the association between the 5-HTR2A polymorphism and verbal fluency in normalcy, and agree with the assumed contribution of genotype A2A2 to the severity of schizophrenia.
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PMID:[Polymorphism of the serotonin receptor (5-HTR2A) gene and verbal fluency in normalcy and schizophrenia]. 1262 48

Schizophrenia is a highly heritable, neurobehavioral disorder; however, the mode of inheritance is complex, and linkage findings have been difficult to replicate. Some consistent linkage findings have emerged on chromosomes 1, 6, 8, 11, 13, 15, and 22. New methods are being developed for candidate gene identification, including the use of neurobiologic phenotypes observed in relatives of persons with schizophrenia. Neuroimaging studies of relatives implicate abnormal hippocampal structure and inefficient prefrontal network functioning, probably representing mild variants of the abnormalities observed in schizophrenia. These characteristics may represent stable markers of vulnerability to schizophrenia, because they are not confounded by effects of antipsychotic drugs or psychosis. Recent studies provide evidence for a small role of the catechol-O-methyltransferase gene on 22q, and the serotonin receptor transporter gene on 17q11-q12 in the development of schizophrenia. Linking genes and brain regions or networks is an important step in identification of the pathophysiology of schizophrenia.
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PMID:Genetically mediated brain abnormalities in schizophrenia. 1268 93

With the use of chlorpromazine and other traditional antipsychotics for psychosis, it was soon discovered that the antipsychotic efficacy of this class of medications was closely associated with their ability to block dopamine D(2) receptors in the brain. This prompted the hypothesis that the etiology of schizophrenia and other psychotic illnesses might be caused by a dysregulation of dopamine. This hypothesis, that the dopamine system explains schizophrenia symptoms, however, is far from complete and the treatment with conventional antipsychotic medications is far from ideal. There has been a great deal of speculation regarding the role of serotonin receptor antagonism in regards to antipsychotic effects. The second generation antipsychotics (SGAs), clozapine, risperidone, olanzapine, quetiapine and ziprasidone all have relatively high serotonin to dopamine binding ratios. Serotonin receptor binding may be important to these drugs' actions, possibly by stimulating dopamine activity in mesocortical pathways. Yet, while the mechanism of action of SGAs as a group remain unsolved, it is important to note that the SGAs offer many clinical benefits to treatment as compared to traditional antipsychotics and are quickly emerging as first-line therapy for schizophrenia. In addition to lower rates of EPS and tardive dyskinesia, other benefits to treatment with this class of antipsychotics include better treatment of negative symptoms, better compliance, possible benefits for cognitive impairments, lower rates of relapse and rehospitalization, and more cost-effective therapy. Within the class of SGAs, however, differences exist both in efficacy and side effects and these will be described. Optimization of treatment and understanding the exact mechanism of action of current antipsychotic medications will help pave the way for new drug targets in the future.
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PMID:Current status of antipsychotic treatment. 1276 30


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