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)

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that mediates a wide range of central nervous functions by activating multiple 5-HT receptor subtypes. A possible irregularity of serotonergic neurotransmission has been implicated in a variety of neuropsychiatric diseases. In the present study, we performed a systematic mutation scan of the complete coding region and splice junctions of the 5-HT(6) receptor gene to explore the contribution of this gene to the development of bipolar affective disorder and schizophrenia. Investigating 137 unrelated individuals (including 45 bipolar affective patients, 46 schizophrenic patients, and 46 unrelated controls), we identified six single base substitutions (126G/T, 267C/T, 873+30C/T, 873+128A/C, 1128G/C, 1376T/G). Comparing frequencies between patients and controls, we observed a significant overrepresentation of the 267C allele among bipolar patients (P=0. 023 not corrected for multiple testing). This finding was followed up in an independent sample of 105 bipolar family trios using a family-based association design. Fifty-one transmissions could be examined. In 30 cases allele 267C and in 21 cases allele 267T were transmitted to the affected offspring. Although this result was far from statistical significance (transmission disequilibrium test=1.59, P=0.208), the limited number of possible transmissions may have prevented detection of smaller effects. Our preliminary data suggest that bipolar affective disorder may be associated with variation in the 5-HT(6) gene. It will be important to extend the present analysis to larger samples. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:217-221, 2000.
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PMID:Investigation of the human serotonin 6 [5-HT6] receptor gene in bipolar affective disorder and schizophrenia. 1089 99

Positron-emission tomography (PET) provides potential in neuropsychiatric drug development by expanding knowledge of drug action in the living human brain and reducing time consumption and costs. The 5-hydroxytryptamine(1A) (5-HT(1A)) receptor is of central interest as a target for the treatment of anxiety, depression, and schizophrenia. Research on the clinical significance of the 5-HT(1A) receptor now benefits from the highly selective radioligand [carbonyl-(11)C]WAY-100635 (WAY) for quantitative determination of 5-HT(1A) receptors in the primate and human brain in vivo using PET. In this paper, three studies are reviewed to demonstrate the suitability of WAY as radioligand for quantification of central 5-HT(1A) receptors in brain and as an applicable tool for drug development. In the first study a monkey model was used to characterize WAY binding. It was confirmed that the reference ligand 8-OH-DPAT and psychoactive drugs such as buspirone and pindolol occupies 5-HT(1A) receptors in the primate brain. Pindolol is an beta-adrenoreceptor antagonist with a high affinity to 5-HT(1A) receptors. This drug has been suggested in combination with selective serotonin reuptake inhibitors for the treatment of depression and was given to healthy males in the second study. Pindolol induced a marked inhibition of central 5-HT(1A) receptors as calculated by the ratio-analysis method and simplified reference tissue model, 2 h after administration of 10 mg as a single oral dose. This observation suggests that pindolol may have a role for the suggested potentiation of selective serotonin reuptake inhibitor treatment of depression. The third study was on robalzotan (NAD-299), a recently developed 5-HT(1A) receptor antagonist and putative drug with implications for the treatment of depression. In the cynomolgus monkey brain, robalzotan in the dose range 2-100 microg/kg IV occupied 5-HT(1A) receptors in a dose-dependent and saturable manner with a maximal calculated occupancy of 70-80%. The relationship between robalzotan plasma concentration and 5-HT(1A) receptor occupancy could be described by a hyperbolic function that was used to guide the selection of appropriate doses in man. In a subsequent PET study of robalzotan binding to 5-HT(1A) receptors in the living human brain, similar results have been replicated recently. These studies reviewed here illustrate and corroborate that quantitative neuroimaging of receptor binding has potential for the evaluation and dose finding of new central nervous system drugs.
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PMID:Use of PET and the radioligand [carbonyl-(11)C]WAY-100635 in psychotropic drug development. 1096 60

Serotonin (5-hydroxytryptamine, 5-HT) appears to play a role in the pathophysiology of a range of neuropsychiatric disorders, and serotonergic agents are of central importance in neuropharmacology. Genes encoding various components of the 5-HT system are being studied as risk factors in depression, schizophrenia, obsessive-compulsive disorder, aggression, alcoholism, and autism. Recently, pharmacogenetic research has begun to examine possible genetic influences on therapeutic response to drugs affecting the serotonin system. Genes regulating the synthesis (TPH), storage (VMAT2), membrane uptake (HTT), and metabolism (MAOA) of 5-HT, as well as a number of 5-HT receptors (HTR1A, HTR1B, HTR2A, HTR2C, and HTR5A), have been studied and this initial research is reviewed here. After a brief introduction to serotonin neurobiology and a general discussion of appropriate genetic methodology, each of the major 5-HT-related genes and their encoded proteins are reviewed in turn. For each gene, relevant polymorphisms and research on functional variants are discussed; following brief reviews of the disorder or trait association and linkage studies, pharmacogenetic studies performed to date are covered. The critical and manifold roles of the serotonin system, the great abundance of targets within the system, the wide range of serotonergic agents-available and in development-and the promising preliminary results suggest that the serotonin system offers a particularly rich area for pharmacogenetic research.
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PMID:Pharmacogenetics and the serotonin system: initial studies and future directions. 1113 68

1. The hippocampal formation plays an important role in the normal functioning of the brain, being implicated in cognition and sensory gating, both of which are affected in schizophrenia. The hippocampal formation receives information from the association cortices, which is processed by glutamatergic transmission within the hippocampus. Dopamine, noradrenaline, 5-hydroxytryptamine (5-HT), acetylcholine and GABA, all of which have been proposed to play a role in the neurobiology of schizophrenia, can affect this transmission. 2. The advent of the 'atypical' antipsychotics, with their broad pharmacological spectra and improved therapeutic outcome, has revitalized research into neurotransmitter dysfunction other than that of dopamine. In particular, there has been interest in the serotonergic and cholinergic systems within the hippocampal formation because these are two of the transmitter systems targeted by clozapine and olanzapine. 3. From the study of these systems, using tissue obtained postmortem from subjects with schizophrenia, we propose that there is a hyperserotonergic state in the hippocampal formation of some subjects with schizophrenia caused by a conformational change in the 5-HT transporter. The model we propose allows us to construct further studies that will test the consequences of such a hyperserotonergic state in the hippocampal formation. This model has the potential to open new avenues in schizophrenia research.
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PMID:A proposed pathological model in the hippocampus of subjects with schizophrenia. 1115 41

1. The pathological process that precipitates schizophrenia has yet to be identified. However, many lines of evidence suggest that a change in the functioning of the frontal cortex is an important abnormality that underlies schizophrenia. 2. Studies in Brodmann's area 9, obtained post-mortem, have shown changes in 5-hydroxytryptamine 5-HT2A, muscarinic M1 and GABA(A) receptors in tissue from subjects with schizophrenia. 3. Animal studies suggest a site in the cortex where there would be an interaction between serotonergic and cholinergic innervation and that this interaction would involve the 5-HT2A and the M1 receptor. This site, in turn, would be a potent modulator of GABA activity and, hence, levels of GABA(A) receptors. 4. From combining these data, a theoretical site is proposed that, if proven to exist in human cortex, is likely to be central to the pathology of that illness.
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PMID:A predicted cortical serotonergic/cholinergic/GABAergic interface as a site of pathology in schizophrenia. 1115 42

1. Schizophrenia is a chronic, disabling brain disease that affects approximately 1% of the world's population. It is characterized by delusions, hallucinations and formal thought disorder, together with a decline in socio-occupational functioning. While the causes for schizophrenia remain unknown, evidence from family, twin and adoption studies clearly demonstrates that it aggregates in families, with this clustering largely attributable to genetic rather than cultural or environmental factors. Identifying the genes involved, however, has proven to be a difficult task because schizophrenia is a complex trait characterized by an imprecise phenotype, the existence of phenocopies and the presence of low disease penetrance. 2. The current working hypothesis for schizophrenia causation is that multiple genes of small to moderate effect confer compounding risk through interactions with each other and with non-genetic risk factors. The same genes may be commonly involved in conferring risk across populations or they may vary in number and strength between different populations. To search for evidence of such genetic loci, both candidate gene and genome-wide linkage studies have been used in clinical cohorts collected from a variety of populations. Collectively, these works provide some evidence for the involvement of a number of specific genes (e.g. the 5-hydroxytryptamine (5-HT) type 2a receptor (5-HT2a) gene and the dopamine D3 receptor gene) and as yet unidentified factors localized to specific chromosomal regions, including 6p, 6q, 8p, 13q and 22q. These data provide suggestive, but no conclusive, evidence for causative genes. 3. To enable further progress there is a need to: (i) collect fine-grained clinical datasets while searching the schizophrenia phenotype for subgroups or dimensions that may provide a more direct route to causative genes; and (ii) integrate recent refinements in molecular genetic technology, including modern composite marker maps, DNA expression assays and relevant animal models, while using the latest analytical techniques to extract maximum information in order to help distinguish a true result from a false-positive finding.
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PMID:Molecular genetics of schizophrenia. 1115 40

Dysfunction of monoamine neurotransmission seems to contribute to such pathopsychological states as depression, schizophrenia, and drug abuse. The present study examined the effects of the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) and antidepressant fluvoxamine on locomotor activity in rats following administration of the catecholamine reuptake inhibitor mazindol. Mazindol (1 mg/kg) did not alter locomotor activity; whereas, fluvoxamine (20 mg/kg) given alone induced a brief period of hypomotility. Hyperactivity was elicited in a dose-related manner when fluvoxamine (5-20 mg/kg) was combined with mazindol (1 mg/kg). The hyperactivity elicited by fluvoxamine (20 mg/kg) plus mazindol (1 mg/kg) was significantly attenuated by the 5-HT(2A) receptor antagonist M100907 (2 mg/kg) and potentiated by the 5-HT(2B/2C) receptor antagonist SB 206553 (2 mg/kg). Neither antagonist significantly altered basal activity. The hyperactivity evoked by the combination of fluvoxamine and mazindol seems to be mediated in part by 5-HT(2A) receptors; whereas, 5-HT(2B/2C) receptors may serve to limit this effect. Thus, the balance of activation between 5-HT(2A) and 5-HT(2B/2C) receptors seems to contribute to the expression of locomotor hyperactivity evoked via combination of a 5-HT and a catecholamine reuptake inhibitor. A disruption in this balance may contribute to the expression of affective disorders, schizophrenia, and drug abuse.
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PMID:Role of 5-HT(2a) and 5-HT(2B/2C) receptors in the behavioral interactions between serotonin and catecholamine reuptake inhibitors. 1116 21

Biogenic amine transporters, namely the dopamine (DA), norepinephrine (NE) and 5-hydroxytryptamine (serotonin, 5-HT) transporters (DAT, NET and 5-HTT, respectively) appear to be the key elements in regulating biogenic amine neurotransmission. These proteins therefore represent a primary target for therapeutic intervention in the treatment of numerous psychiatric disorders, such as depression, anxiety and perhaps even schizophrenia as well as drug abuse. The cloning of DAT, NET and 5-HTT and development of selective radioligands for them over the last decade has dramatically increased our understanding of their location, structure and function. These breakthroughs have also enabled remarkable progress in determining how biogenic amine transporters are regulated under not only normal conditions but also when confronted with acute or chronic exposure to a variety of stimuli including psychotherapeutic drugs. Because of the important therapeutic consequences of a better understanding of these transporters, the present review discusses recent advances in defining their mechanism of action, location and regulation and the implications of the newer data for neuropsychopharmacology.
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PMID:New views of biogenic amine transporter function: implications for neuropsychopharmacology. 1128 47

SB-243213 (5-methyl-1-[[-2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline hydrochloride) is a new, selective 5-hydroxytryptamine (5-HT)2C receptor inverse agonist. SB-243213 has high affinity for the human 5-HT2C receptor (pK(i) 9.37) and greater than a 100-fold selectivity over a wide range of neurotransmitter receptors, enzymes and ion channels. In in vitro functional studies, SB-243213 acted as an inverse agonist at the human 5-HT2C receptor with a pK(b) of 9.8. In in vivo studies, SB-243213 was a potent inhibitor of central 5-HT2C receptor-mediated function in rats, blocking meta-chlorophenylpiperazine-induced hypolocomotion with an ID50 of 1.1 mg/kg p.o. and a long duration of action (>8 h). In rats, SB-243213 exhibited anxiolytic-like activity in both the social interaction and Geller-Seifter conflict tests. Importantly, unlike diazepam, chronic administration of SB-243213 did not result in the development of either tolerance to the anxiolytic-like effects or withdrawal anxiogenesis. Furthermore, in rodents, SB-243213 did not affect seizure threshold, did not increase body weight or induce catalepsy, but attenuated the haloperidol-induced catalepsy. SB-243213 did not affect amphetamine-, MK-801- or phencyclidine-induced hyperactivity. In conclusion, SB-243213 may possess an improved anxiolytic profile compared to benzodiazepines. SB-243213 also modulates dopaminergic transmission, lacks pro-psychotic properties and may have utility in the treatment of schizophrenia and motor disorders.
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PMID:SB-243213; a selective 5-HT2C receptor inverse agonist with improved anxiolytic profile: lack of tolerance and withdrawal anxiety. 1148 55

Atypical antipsychotic drugs, which are distinguished from typical antipsychotic drugs by a lower incidence of extra-pyramidal side effects and less propensity to elevate serum prolactin levels (e.g., clozapine, olanzapine, risperidone, quetiapine, ziprasidone), have become the most widely used treatments for schizophrenia, although their precise mechanism of action remains controversial. It has been suggested that this group of atypical antipsychotic drugs is characterized by preferentially high affinities for 5-hydroxytryptamine (5-HT)2A serotonin receptors and relatively low affinities for D2-dopamine receptors. It has recently been proposed that these atypical antipsychotic drugs may also be distinguished from typical antipsychotic drugs (e.g., haloperidol, fluphenazine, chlorpromazine, and so on) by inverse agonist actions at the 5-HT2C-INI RNA edited isoform of the human 5-HT2C receptor transiently expressed in COS-7 cells. We have examined the relationship among 5-HT2C inverse agonist potency, efficacy, and atypical antipsychotic drug status in HEK-293 cells of a large number of typical and atypical antipsychotic drugs using human embryonic kidney (HEK)-293 cells stably transfected with the h5-HT2C-INI receptor. Inverse agonist actions at h5-HT2C-INI receptors were measured for both typical and atypical antipsychotic drugs. Thus, some typical antipsychotic drugs (chlorpromazine, mesoridazine, fluphenazine, and loxapine) were efficient inverse agonists, whereas several clinically effective atypical antipsychotic drugs (remoxapride, quetiapine, sulpiride, melperone, amperozide) were not. Additionally, several drugs without significant antipsychotic actions (M100907, ketanserin, mianserin, ritanserin, and amitriptyline) were potent inverse agonists at the 5-HT2C-INI isoform expressed in HEK-293 cells. Taken together, these results demonstrate that both typical and atypical antipsychotic drugs may exhibit inverse agonist effects at the 5-HT2C-INI isoform of the human 5-HT2C receptor and that no relationship exists between inverse agonist actions and atypicality.
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PMID:Inverse agonist actions of typical and atypical antipsychotic drugs at the human 5-hydroxytryptamine(2C) receptor. 1156 Oct 66


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