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)

Synaptic neurotransmission in the central nervous system (CNS) requires the precise control of the duration and the magnitude of neurotransmitter action at specific molecular targets. At the molecular level, neurotransmitter signaling is dynamically regulated by a diverse set of macromolecules including biosynthetic enzymes, secretory proteins, ion channels, pre- and postsynaptic receptors and transporters. Monoamines, 5-hydroxytryptamine or serotonin (5-HT), norepinephrine (NE), and dopamine (DA) play an important modulatory role in the CNS and are involved in numerous physiological functions and pathological conditions. Presynaptic plasma membrane transporters for 5-HT (SERT), NE (NET), and DA (DAT), respectively, control synaptic actions of these monoamines by rapidly clearing the released amine. Monoamine transporters are the sites of action for widely used antidepressants and are high affinity molecular targets for drugs of abuse including cocaine, amphetamine, and 3,4-methylenedioxymetamphetamine (MDMA) "Ecstasy." Monoamine transporters also serve as molecular gateways for neurotoxins. Emerging evidence indicates that regulation of transporter function and surface expression can be rapidly modulated by "intrinsic" transporter activity itself, and antidepressant and psychostimulant drugs that block monoamine transport have a profound effect on transporter regulation. Therefore, disregulations in the functioning of monoamine transporters may underlie many disorders of transmitter imbalance such as depression, attention deficit hyperactivity disorder, and schizophrenia. This review integrates recent progress in understanding the molecular mechanisms of monoamine transporter regulation, in particular, posttranscriptional regulation by phosphorylation and trafficking linked to cellular protein kinases, protein phosphatases, and transporter interacting proteins. The review also discusses the possible role of psychostimulants and antidepressants in influencing monoamine transport regulation.
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PMID:Regulation of monoamine transporters: influence of psychostimulants and therapeutic antidepressants. 1635 49

Evidence is increasing for a role of brain 5-hydroxytryptamine (5-HT) systems in schizophrenia. We previously showed that brain 5-HT depletion causes disruption of prepulse inhibition, a measure of sensorimotor gating that is deficient in schizophrenia. Antipsychotic treatment has been reported to reverse these deficits in patients with schizophrenia. The present study was designed to investigate the ability of antipsychotic drugs to reverse prepulse inhibition deficits caused by lesions of the brain 5-HT system in rats. In male Sprague-Dawley rats, selected parts of the brain 5-HT systems were lesioned by micro-injection of the 5-HT neurotoxin 5,7-dihydroxytryptamine into the dorsal raphe nucleus (DRN) or median raphe nucleus (MRN). The effects of antipsychotic drugs on lesion-induced changes in prepulse inhibition were examined 2 weeks after the surgery. There was significant disruption of prepulse inhibition in the MRN-lesioned group compared to sham-operated controls. This deficiency in prepulse inhibition was restored by clozapine (1 and 5 mg kg(-1)) treatment, and by treatment with a relatively high dose of haloperidol (0.25 mg kg(-1)). There was no significant effect of the DRN lesions on prepulse inhibition compared with sham-operated controls. These results indicate that 5-HT depletion in MRN-innervated brain structures leads to disruption of prepulse inhibition. Treatment with both antipsychotic drugs, haloperidol and clozapine, significantly increased prepulse inhibition in these animals back to the level seen in sham-operated controls. The present findings highlight the importance of the 5-HT systems in cognitive models of schizophrenia.
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PMID:Effects of haloperidol and clozapine on sensorimotor gating deficits induced by 5-hydroxytryptamine depletion in the brain. 1641 9

The serotonin (5-hydroxytryptamine) 5-HT2 receptor subfamily consists of three members, 5-HT2A, 5-HT2B, and 5-HT2C. These receptors share high homology in their amino acid sequence, have similar signaling pathways, and have been indicated to play important roles in feeding, anxiety, aggression, sexual behavior, mood, and pain. Subtype-selective agonists and antagonists have been explored as drugs for hypertension, Parkinson's disease, sleep disorders, anxiety, depression, schizophrenia, and obesity. In this study, we report the development of homogeneous agonist binding assays in a scintillation proximity assay (SPA) format to determine the high-affinity binding state of agonist compounds for the human 5-HT2C, 5-HT2A, and 5-HT2B receptors. The 5-HT2 agonist 1-(4- [125I]iodo-2,5-dimethoxyphenyl)-2-aminopropane ([125I]DOI) was used to label the high-affinity sites for the 5-HT2A and 5-HT2C receptors. The high-affinity sites for the 5-HT2B receptor were labeled with [3H]lysergic acid diethylamide. Total receptor expression was determined with the 5-HT2 antagonist [3H]mesulergine for the 5-HT2B and 5-HT2C receptors, and [3H]ketanserin for the 5-HT2A receptor. The agonist high-affinity binding sites accounted for 2.3% (5-HT(2C) receptor), 4.0% (5-HT2A receptor), and 22% (5-HT2B receptor) of the total receptor population. Competition binding studies using known agonists indicated high Z' values of the agonist binding assays in SPA format (Z' > 0.70). The Ki values of 5-HT, (R)(-)DOI, and VER-3323 for the 5-HT2A, 5-HT2B, and 5-HT2C receptors by SPA format were equivalent to published data determined by filtration binding assays. These results indicate that agonist binding assays in SPA format can be easily adapted to a high throughput assay to screen for selective 5-HT2C receptor agonists, as well as for selectivity profiling of the compounds.
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PMID:Development of homogeneous high-affinity agonist binding assays for 5-HT2 receptor subtypes. 1643 60

Although the 5-hydroxytryptamine(6) (5-HT(6)) receptor was discovered only recently, its almost exclusive distribution in the brain makes it a promising, novel, target for central nervous system (CNS)-mediated diseases such as Alzheimer's disease (cognitive function), schizophrenia, anxiety and obesity. In the past few years a significant research interest has advanced the understanding of the functional roles and the pharmacophore requirements of this receptor. Two 5-HT(6) receptor antagonists have already entered Phase II clinical trials for the enhancement of cognitive function. Since the first discovery of selective ligands for the 5-HT(6) receptor by HTS in 1998, several medicinal-chemistry-driven approaches have delivered highly selective lead structures with well-defined functionalities, starting from either the endogenous ligand 5-HT or the chemical structures identified by HTS. The concept of 'scaffold hopping' has been employed to expand the variability of the available chemical scaffolds and to generate patentable ligands. Supported by pharmacophore models, which have been established recently, the binding and functionality (structure-activity relationships) of the lead structures have been optimized further.
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PMID:Medicinal chemistry strategies to 5-HT(6) receptor ligands as potential cognitive enhancers and antiobesity agents. 1658 Sep 70

Ziprasidone is a second-generation antipsychotic currently marketed for the treatment of schizophrenia and bipolar mania. It has a unique receptor profile that includes high-affinity antagonist activity at 5-hydroxytryptamine (5-HT) 2A, D2, 1D and 2C receptors, a potent agonist activity at 5-HT1A receptors and a relatively high affinity for the 5-HT and noradrenaline transporters. The efficacy of ziprasidone in bipolar mania (current episode, manic or mixed) has been well demonstrated in three placebo-controlled trials. In a three-arm controlled study, ziprasidone was shown to be efficacious in dysphoric mania, whereas haloperidol was comparable to placebo. Open-label treatment for up to 52 weeks supported the sustained efficacy of ziprasidone in bipolar disorder. Combined with lithium, ziprasidone has been shown to be efficacious as an augmenting agent in the acute treatment of mania, with sustained efficacy up to 1 year. Ziprasidone was very well tolerated by patients with bipolar disorder and did not cause increased weight, glucose or lipid levels.
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PMID:Ziprasidone in bipolar disorder. 1673 8

Antipsychotic drugs (APD) are widely prescribed for the treatment of schizophrenia. The APD are differentiated into typical and atypical based on the lower incidence of extra-pyramidal side-effects associated with the newer atypical APD. It was suggested that atypicality may arise from an interaction with the 5-hydroxytryptamine (5-HT)(2) receptor and specifically on the 5-HT(2):dopamine D(2) affinity ratio. It is now realised that multiple subtypes of these receptors exist and that in addition, atypical APD interact with many monoamine receptors. The aim of the present study was to characterise the interaction of APD with a variety of monoamine receptors in terms of both affinity and efficacy. The data produced has highlighted that the atypical profile of APD such as olanzapine and clozapine may reflect antagonism of the 5-HT(2A) and 5-HT(2C) receptors, whilst that of, ziprasidone and quetiapine may reflect partial agonist activity at the 5-HT(1A) receptor, and that of aripiprazole may reflect partial agonist activity at the 5-HT(1A) receptor as well as is its claimed partial agonist activity at the dopamine D(2) receptor.
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PMID:Pharmacological profile of antipsychotics at monoamine receptors: atypicality beyond 5-HT2A receptor blockade. 1691 96

Cortical metabotropic glutamate receptors (mGluRs) seem to be involved in habituation of simple stimulus-bound behaviors (e.g., habituation to acoustic startle or odor-elicited orienting response). Habituation deficits may contribute to the cognitive symptoms of schizophrenia. In the present study, male NMRI mice were injected with mGluR2/3 antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid (LY-341495) 30 min before being placed into novel arenas for automatic motor activity recording (2-h sessions). Administration of LY-341495 (1-10 mg/kg s.c.) dose-dependently prevented the habituation of the locomotor activity. Effects of LY-341495 (10 mg/kg) were fully and dose-dependently reversed by i.p. administration of haloperidol (0.03-0.3 mg/kg), clozapine (1-10 mg/kg), risperidone (0.01-0.1 mg/kg), olanzapine (0.3-3 mg/kg), aripiprazole (1-10 mg/kg), and sulpiride (3-30 mg/kg), each of which was given 15 min before the test. Effects of antipsychotic drugs were observed at the dose levels that did not affect spontaneous motor activity. LY-341495-induced delayed hyperactivity was also partially attenuated by lithium (50-200 mg/kg), amisulpride (1-10 mg/kg), and the selective dopamine D3 antagonist trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011A; 3-30 mg/kg). Application of diazepam, imipramine, or several agonists and/or antagonists acting at various receptors that are thought to be relevant for antipsychotic treatment [e.g., 5-hydroxytryptamine (5-HT)(2A), 5-HT(3), and 5-HT(6) antagonists; 5-HT(1A) agonist; D4 antagonist; CB1 antagonist; ampakines; and glycine transporter inhibitor) had no appreciable effects. Thus, behavioral deficits induced by mGluR2/3 blockade (such as delayed motor hyperactivity) are selectively reversed by clinically used antipsychotic drugs.
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PMID:Habituation deficits induced by metabotropic glutamate receptors 2/3 receptor blockade in mice: reversal by antipsychotic drugs. 1713 47

Suicidal behavior is a major health risk in psychiatric disorders, especially in schizophrenia, wherein up to 10% patients will commit suicide. However, the neurobiology of suicide is still unclear. Suicidality has been related to decreased central serotonergic (5-hydroxytryptamine, 5-HT) function and reduced cholesterol levels. Platelet 5-HT has been used as a peripheral marker of the central serotonergic synaptosomes. The aim of this study was to evaluate serum cholesterol and platelet 5-HT concentrations in suicidal and non-suicidal men in the first episode of psychosis and in healthy male controls. Venous blood samples were collected within 24 h of admission, and serum cholesterol and platelet 5-HT were determined enzymatically and fluorimetrically. Platelet 5-HT and serum cholesterol concentrations were significantly lower in suicidal than in non-suicidal patients in the first episode of psychosis, and also lower than in healthy controls. Our results suggest that lower concentrations of serum cholesterol and platelet 5-HT in patients with a first episode of psychosis might be useful biological markers of suicidality.
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PMID:Platelet serotonin and serum cholesterol concentrations in suicidal and non-suicidal male patients with a first episode of psychosis. 1727 Feb 80

It was previously reported that brain areas containing serotonin (5-hydroxytryptamine, 5-HT) receptors mediate memory consolidation as well as short (STM)- and long-term memory (LTM). Here the effects of systemic and intrahippocampal administration of 5-HT agonists and antagonists on an autoshaping learning task were explored, which requires hippocampal translation and transduction as well as 5-HT receptors expression. As previously reported ketamine (glutamatergic antagonist) and two well-known amnesic drugs, scopolamine (cholinergic antagonist) and dizocilpine (NMDA antagonist) impaired STM but not LTM; dizocilpine even improved the latter. Since ketamine produces hallucinations and impairs memory in humans, we address the question if well-known antipsychotic haloperidol and clozapine might affect STM deficit. Indeed, systemic administration of clozapine<haloperidol reversed the ketamine-STM deficit. Considering that clozapine and haloperidol are antagonists for dopaminergic D2 and 5-HT(1A/2A/6/7) receptors, systemic and intrahippocampal administration of 5-HT drugs were further explored. The ketamine STM-induced deficit was blocked by 8-OHDPAT (5-HT(1A/7) agonist) and SB-399885 (a 5-HT(6) antagonist) but not by 5-HT(1B), 5-HT(2) and 5-HT(7) antagonists, thus implicating 5-HT(1A/7) and 5-HT(6) receptors. These data also suggest that ketamine (at 10 mg/kg) represents a reliable pharmacological tool to explore memory deficits related to hippocampus and schizophrenia.
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PMID:Role of 5-HT1-7 receptors in short- and long-term memory for an autoshaping task: intrahippocampal manipulations. 1736 30

Tardive dyskinesia (TD), a syndrome of involuntary hyperkinesias in the orofacial region that develops in patients chronically treated with neuroleptic agents is a major limitation of the therapy. Rats chronically treated with haloperidol exhibit vacuous chewing movements (VCMs) with the twitching of facial musculature and tongue protrusion. The syndrome is widely used as an animal model of TD. Evidence suggests a role of 5-hydroxytryptamine (5-HT; serotonin)-1A receptors in the pathogenesis and treatment of TD because repeated administration of haloperidol resulted in an increase in the effectiveness of 5-HT-1A receptors while drugs with agonist activity at 5-HT-1A receptors could attenuate haloperidol-induced VCMs. The present study was designed to test the hypothesis that a decrease in the responsiveness of somatodendritic 5-HT-1A receptors by the coadministration of buspirone could reverse the induction of VCMs and supersensitivity at 5-HT-1A receptors by haloperidol. Rats treated with haloperidol at a dose of 1 mg/kg twice a day for 2 weeks displayed VCMs with twitching of facial musculature that increased in a time dependent manner as the treatment continued to 5 weeks. Coadministration of buspirone attenuated haloperidol-induced VCMs after 2 weeks and completely prevented it after 5 weeks. The intensity of 8-hydroxy-2-di (n-propylamino) tetralin (8-OH-DPAT)-induced locomotion was greater in saline+haloperidol injected animals but not in buspirone+haloperidol injected animals. 8-OH-DPAT-induced decreases of 5-HT metabolism were greater in saline+haloperidol injected animals but not in buspirone+haloperidol injected animals. It is suggested that an impaired somatodendritic 5-HT-1A receptor dependent response is a major contributing factor in the pathophysiology of TD and a normalization of the somatodendritic response by drugs may help extending therapeutics in schizophrenia.
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PMID:Reversal of haloperidol-induced tardive vacuous chewing movements and supersensitive somatodendritic serotonergic response by buspirone in rats. 1749 86


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