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)

The discovery of chlorpromazine led to rapid progress in drug therapy for schizophrenia. However, conventional neuroleptics frequently induce EPS and tardive dyskinesia in addition to the drawback of having little effect against negative symptoms. New types of atypical antipsychotics has been actively developed in Japan to overcome these drawbacks. Firstly, serotonin-dopamine antagonist (SDA) is most actively developed. Eight SDAs have been introduced into clinical trials: risperidone's trials have been finished and a NDA has been filed, Org 5222 has been dropped because of worsening of significant cases, and 6 SDAs (SM-9018, sertindole, seroquel, AD-5423, ziprasidone and olanzapine) are now under development. Secondly, OPC-14597, a unique atypical antipsychotic has been advanced to the phase 3 study, which has both DA autoreceptor-agonistic and D2-receptor blocking actions. Thirdly, we have much interest in NE-100, a selective sigma receptor antagonist which potently suppresses the phencyclidine-induced behaviors. Finally. a 5-HT3 receptor antagonist, alosetron was already dropped because it showed no antipsychotic effects, although it was introduced with great expectations. We hope that as many as possible new antipsychotics will be approved for the battle against schizophrenia.
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PMID:[Recent progress in development of psychotropic drugs (2)--antipsychotics]. 758 13

This article reviews current knowledge on the interaction between 5-hydroxytryptamine (5-HT), acting at 5-HT3 receptors in the CNS, and cerebral dopamine systems. Since 1987, a growing body of behavioural, neurochemical and electrophysiological evidence from animal studies has demonstrated a clear role for 5-HT3 receptors in the modulation of activity of mesolimbic and mesocortical dopamine neurones. This evidence has led to the suggestion that 5-HT3 receptor antagonists have potential as novel antipsychotic agents and may also find use in the treatment of psychoactive substance abuse. Data emerging from clinical studies generally support this hypothesis and suggest that 5-HT3 antagonists may prove to be among the first agents available to treat schizophrenia which are not dopamine D2 antagonists and hence lack their side-effect problems.
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PMID:Interactions between 5-HT3 receptors and cerebral dopamine function: implications for the treatment of schizophrenia and psychoactive substance abuse. 783 43

The pharmacology of 5-HT and the classification of 5-HT receptors have become increasingly complex. However, recent advances have produced a new nomenclature system for 5-HT receptors. 5-HT3 receptors are neuronal receptors coupled directly to cation channels. Recently, many selective 5-HT3-receptor antagonists including tropisetron, zacopride, ondansetron, granisetron, zatosetron, nazasetron, YM060 and YM114 (KAE-393) have been developed. Many actions attributable to the 5-HT3-receptor have been described in both the peripheral and central nervous systems, and clinical trials are already showing the potential use of these 5-HT3 receptor antagonists in a number of disorders of the gastrointestinal tract and central nervous system, such as nausea and vomiting induced by cancer chemotherapy, anxiety, depression, schizophrenia and migraine. In addition, endogenous 5-HT is suggested to be one of the substances that mediate stress-induced responses in gastrointestinal function, i.e., increase in fecal pellet output and diarrhea. Moreover, YM060, YM114 (KAE-393) and granisetron have been reported to inhibit restraint stress- and 5-HT-induced increases in fecal pellet output and diarrhea in rats and mice, indicating that endogenous 5-HT may mediate stress-induced changes in bowel function through the 5-HT3 receptor. Therefore, 5-HT3-receptor antagonists are new therapeutic drugs for stress-induced gastrointestinal dysfunctions like irritable bowel syndrome (IBS).
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PMID:[Serotonin (5-HT)3 receptors: antagonists and their pharmacological profiles]. 795 7

There has been tremendous interest in 5-HT3 receptor antagonists since their discovery and the subsequent identification of 5-HT3 receptors in the CNS. Based on the results of early behavioural tests with these compounds, there has been substantial interest in their potential use for the treatment of various CNS disorders. In this review, Andrew Greenshaw attempts to clarify the status of the therapeutic potential of these drugs, discussing inconsistencies in preclinical findings and identifying areas in need of clarification through future research. 5-HT3 receptor antagonists are claimed to be potentially useful in the treatment of nausea, inflammatory pain (migraine and irritable bowel syndrome), anxiety, depression, schizophrenia, dementia and drug abuse!
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PMID:Behavioural pharmacology of 5-HT3 receptor antagonists: a critical update on therapeutic potential. 810 96

The octapeptide cholecystokinin (CCK) is one of the most abundant neuropeptides of the central nervous system. A number of features (for instance heterogeneity of the regional distribution, subcellular localization at the nerve terminal level, calcium-dependent release upon nervous tissue depolarization) support the candidacy of CCK as a neurotransmitter. The reported co-existence of CCK and dopamine in some meso-limbic neurons has led to speculation that the neuropeptide may interact with the catecholamine in neuropsychopathologies linked to dopamine dysfunctions, like schizophrenia. Data from the experimental animals have so far generated conflicting results. It should be noted that the interactions between CCK and dopamine, and, in particular, the effects of CCK and dopamine on each other release, both in vitro and in vivo, have been poorly investigated and would require special attention. Evidence is accumulating that CCK may participate in the expression of anxiety. Indeed antagonists at the central CCK receptors exhibit anxiolytic activity in the laboratory animal. An interesting linkage appears to exist in the brain between 5-hydroxytryptamine (5-HT) and CCK. Activation of 5-HT3 receptors was found to increase CCK release from rat cortical or nucleus accumbens synaptosomes. Interestingly, antagonists at 5-HT3 receptors appear to possess anxiolytic activity. Recent studies carried out in conscious unrestrained rats show that the calcium-dependent, tetrodotoxin-sensitive release of CCK-like immunoreactivity evoked in the rat frontal cortex by veratrine infusion can be inhibited by submicromolar concentrations of 5-HT3 receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Release of cholecystokinin in the central nervous system. 851 79

Clozapine is an atypical antipsychotic drug active on both positive and negative symptoms of schizophrenia which has a unique serotonergic and dopaminergic profile. Given the putative role of the medial prefrontal cortex (mPFC) in negative symptoms of schizophrenia, the aim of this study was to assess the effects of clozapine on the dopamine- and serotonin-responsive neurons in that particular brain structure. D1 and D2 agonists (SKF 38393 and quinpirole) as well as 5-HT2 and 5-HT3 agonists (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, DOI, and phenylbiguanide) were applied by microiontophoresis alone and concurrently with clozapine while recording extracellularly mPFC neurons. Dopamine ejections inhibited firing activity while D1 and D2 agonists were ineffective. Clozapine did not change basal firing by itself, but was able to suppress the inhibition produced by dopamine and by the 5-HT2/5-HT3 receptor agonists. It is concluded that clozapine at the mPFC level exerts a complex modulatory activity on dopamine receptors, that is directly at the dopaminergic receptors and through 5-HT receptors on the same neurons.
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PMID:Clozapine blocks dopamine, 5-HT2 and 5-HT3 responses in the medial prefrontal cortex: an in vivo microiontophoretic study. 1064 96

5-HT research is now more than 50 years old, and it has generated a wealth of therapeutic agents, some of which have had a major impact on disease management. The 5-HT reuptake inhibitors (SSRIs) are among the most widely prescribed drugs for treating depression and a variety of other disorders including anxiety, social phobia and premenstrual dysphoria (PMD). The other major success stories of 5-HT research are the discovery of 5-HT1B/D receptor agonists for treating migraine and 5-HT3 receptor antagonists for chemotherapy and radiation-induced emesis. The role of 5-HT in the mechanism of action of antipsychotic agents remains a topic of intense research, which promises better treatments for schizophrenia in the future. Compounds interacting with 5-HT1F, 5-HT2C, 5-HT6 and 5-HT7 receptors are currently under investigation and may prove to have important therapeutic applications in the future.
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PMID:The medical benefit of 5-HT research. 1188 47

Clozapine is a potent antagonist of 5-HT3 receptors, which are ligand-gated ion channels that mediate rapid excitatory responses in the central nervous system. Two different isoforms of 5-HT3 receptor subunit genes (HTR3A and HTR3B) have been identified. They have been assigned to chromosome 11q23.1-q23.2, a region which in the past has been linked to schizophrenia and bipolar disorder. In this study, we performed a systematic mutation screening of the 5-HT3A and 5-HT3B receptor genes and tested the variants for association with clozapine response in a sample of 266 clozapine-treated patients. Two polymorphisms at the 5-HT3A gene and five new variants in the 5-HT3B gene were finally detected. Of these, only the more frequent mutations (178-C/T and 1596-A/G in 5-HT3A and a CA-repeat in 5-HT3B) were genotyped in our clozapine sample. Association analysis showed similar allele and genotype distributions among clozapine responders and nonresponders. These results make unlikely the possibility that 5-HT3A and 5-HT3B receptor genes underlie variation in clinical response to clozapine. However, the promoter regions of both genes have yet to be investigated.
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PMID:Novel mutations in 5-HT3A and 5-HT3B receptor genes not associated with clozapine response. 1236 96

The 5-HT3A receptor, a ligand-gated ion channel, is involved in pain pathways, nausea and emesis, and irritable bowel syndrome, and may play a role in the pathogenesis of psychiatric diseases such as schizophrenia and depression. Recently, a naturally occurring variation (ProArg) in the second intracellular loop of the human (h) 5-HT3A receptor was identified in a schizophrenic patient. Because the substitution of proline, an alpha-imino acid, by arginine may affect the conformation of the whole receptor, the aim of the present study was to determine the pharmacological and functional properties of this variant compared to the wild-type receptor in stably transfected HEK293 cells. Studies of binding of [H]GR65630, a 5-HT3 receptor antagonist, to membranes (saturation and competition experiments with 5-HT3 receptor ligands) and patch-clamp studies of agonist-induced currents in outside-out patches were carried out. In comparison to the wild-type, the variant receptor exhibited no changes in the receptor density and the affinities for nine representative ligands (five agonists and four antagonists). The potencies and efficacies of three 5-HT3 receptor agonists in inducing currents through the ion channel and the potencies of two 5-HT3 receptor antagonists in blocking 5-HT-evoked currents did not differ between wild-type and variant receptors. In addition, there were no differences in the desensitization kinetics of both receptor isoforms. In conclusion, the ArgPro variation of the h5-HT3A receptor does not change ligand binding to the h5-HT3A receptor, nor does it modify current through the receptor channel.
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PMID:Pharmacological and electrophysiological properties of the naturally occurring Pro391Arg variant of the human 5-HT3A receptor. 1516 4

It has been well established that patients with schizophrenia have impaired cognitive function on neuropsychological tasks related to memory. Previous studies also suggest serotonin's central role in memory. This double-blind crossover study aimed to explore the effect of Ondansetron, a selective serotonin 3 receptor (5-HT(3)) antagonist, on a variety of memory tasks in schizophrenic patients. Clozapine-treated schizophrenic patients in remission (N=21) were randomly treated with Ondansetron or placebo and then evaluated at three consecutive points. These evaluations included clinical measures (including Positive and Negative Syndrome Scale for Schizophrenia, Clinical Global Impression and Extrapyramidal Symptoms Rating Scale) and neuropsychological measures (including Digit Span, Paired Association, Rey-Osterich Complex Figure Test, Digit Symbol and the Rivermead Behavioral Memory Tests). Ondansetron, when compared with placebo, did not affect the above clinical measures and most of the neuropsychological tests. Short-term administration of Ondansetron, however, was associated with significantly improved visuo-spatial memory as measured by the Rey-Osterich Complex Figure Test. These preliminary results suggest Ondansetron's possible role in enhancement of memory function in schizophrenia.
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PMID:The effect of Ondansetron on memory in schizophrenic patients. 1581 93


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