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)

A rapidly growing body of data suggests that dysfunction in serotonergic (5-HT) function may be involved in the pathophysiology of schizophrenia, and that pharmacologic agents for this illness have their therapeutic effects mediated through serotonergic mechanisms. The purpose of this paper is to critically review data relevant to 5-HT's role in the pathophysiology and drug treatment of schizophrenia. Pathophysiologic evidence includes the psychotomimetic effects of lysergic acid (LSD), postmortem studies, single-dose 'challenge' studies and investigations of CSF and peripheral levels of 5-HT and its metabolites. The current nomenclature, potential therapeutic effects and importance of 5-HT receptor subtype antagonism will be examined. In addition, relatively novel strategies of 5-HT uptake blockade and direct acting 5-HT agonists will be assessed. A hypothesis of cortical-subcortical imbalance with an increase in subcortical 5-HT function responsible for positive symptoms and a decrease in prefrontal 5-HT function responsible for negative symptoms is proposed. Future implications of these data are discussed.
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PMID:Serotonin, schizophrenia and antipsychotic drug action. 753 88

Serotonin (5-hydroxytryptamine, 5-HT) receptors as well as dopamine receptors are important in connection with schizophrenia. In this study we evaluated the effects of the 5-HT1A receptor agonist (8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT) and 5-HT1B receptor agonist (1-(3-trifluoromethylphenyl)piperazine, TFMPP) on the single and paired rats' movement distance in an open-field. Generally animals are gregarious in their natural setting, so the presence of another companion might alter the effects of the drugs. Therefore we devised a video analysis system to pick up the two rats' movements individually through two CCD video cameras and objectively recorded two rats' movement for 30 minutes. Experimental rats were injected with 8-OH-DPAT (0.05, 0.25, 1.25, 6.25 mg/kg, s.c.) or TFMPP (0.12, 0.5, 2.0, 8.0 mg/kg, i.p.) and the control rats were injected with saline. In the single cases experiments, the rats were put alone into the open field after the injection. In the paired cases experiments, they were put into the open field with a companion rat after the injection. In the 8-OH-DPAT experiment, the movement distance of single cases showed dose dependent increase tendency and that of the 1.25 mg/kg group and the 6.25 mg/kg group showed significant increase, but that of paired cases did not show that tendency, on the contrary, the movement distance of 0.05 mg/kg group showed significant decrease. In the TFMPP experiment, the movement distance of 2.0 mg/kg groups showed significant increases in the single and the paired cases. These findings suggest that both 5-HT1A receptors and 5-HT1B receptors affect the rats' movement distance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Effects of 5-HT1A receptor agonist and 5-HT1B receptor agonist on single and paired rats' behavior]. 754 36

Iloperidone (1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- piperidinyl]propoxy]-3-methoxyphenyl]ethanone) demonstrated a potent antipsychotic profile in several in vitro and in vivo animal models. Iloperidone displaced ligand binding at D2 dopamine receptors (IC50 = 0.11 microM) and displayed a high affinity for serotonin (5-HT2) receptors (IC50 = 0.011 microM) and alpha-1 receptors (IC50 = 0.00037 microM). In vivo, iloperidone antagonized apomorphine-induced climbing behavior in mice at low doses with good oral bioavailability, prevented 5-HT-induced head twitch in rats at low doses, and inhibited self-stimulation behavior in rats, pole climb avoidance in rats and continuous Sidman avoidance responding in monkeys. The latter assay also demonstrated a good duration of action. Iloperidone was substantially less active in models of extrapyramidal side effect (EPS) liability, such as preventing apomorphine-induced stereotypy and causing catalepsy in rats. In single dopamine neuron sampling studies, iloperidone demonstrated clozapine-like effects on the number of active midbrain dopamine neurons. Based on the significant increase in the open arm time seen after iloperidone treatment in the elevated plus maze assay and increased interaction score in social interaction, iloperidone may also have favorable effects in the clinic on anxiety and, possibly, negative symptoms. Clinical trials are under way of the use of iloperidone for the treatment of schizophrenia.
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PMID:The pharmacological profile of iloperidone, a novel atypical antipsychotic agent. 756 15

Ziprasidone (CP-88,059) is a combined 5-HT (serotonin) and dopamine receptor antagonist which exhibits potent effects in preclinical assays predictive of antipsychotic activity. Whereas the compound is a dopamine antagonist in vitro and in vivo, its most potent action is antagonism of 5-HT2A receptors, where its affinity is an order of magnitude greater than that observed for dopamine D2 sites. Laboratory and clinical findings have led to a hypothesis that antagonism of 5-HT2A receptors in the brain limits the undesirable motor side effects associated with dopamine receptor blockade and improves efficacy against the negative symptoms of schizophrenia. Ziprasidone possesses an in vitro 5-HT2A/dopamine D2 receptor affinity ratio higher than any clinically available antipsychotic agent. In vivo, ziprasidone antagonizes 5-HT2A receptor-induced head twitch with 6-fold higher potency than for blockade of d-amphetamine-induced hyperactivity, a measure of central dopamine D2 receptor antagonism. Ziprasidone also has high affinity for the 5-HT1A, 5-HT1D and 5-HT2C receptor subtypes, which may further enhance its therapeutic potential. The prediction of antipsychotic efficacy without severe motor side effects is supported by the relatively weak potency of ziprasidone to produce catalepsy in animals, contrasted with its potent antagonism of conditioned avoidance responding and dopamine agonist-induced locomotor activation and stereotypy. The compound is well tolerated in animals at doses producing effective dopamine antagonism in the brain. Ziprasidone should be a valuable addition to the treatment of psychotic disorders.
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PMID:Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity. 756 37

Clozapine is the first of a new generation of antipsychotic drugs which constitutes a major advance in the treatment of schizophrenia. Numerous theories have been proposed to explain the advantages of clozapine over typical neuroleptics. Most of these focus on its effects on dopaminergic and serotonergic neurotransmission. This article reviews the effects of clozapine and related antipsychotic drugs on dopamine (DA) D1, D2, and D4, and serotonin (5-HT) 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptors, as well as its ability to modulate DA and 5-HT release. Clozapine and other atypical antipsychotic drugs share the ability to cause fewer extrapyramidal symptoms at clinically effective doses. This may be related to their potent 5-HT2A and weak D2 receptor blocking properties, a profile shared by risperidone, melperone, olanzapine, amperozide, HP-873, seroquel, sertindole, and ziprasidone. The basis for the superior ability of clozapine to treat negative symptoms and enhance cognitive function compared to typical neuroleptic drugs in schizophrenic patients has not yet been ascertained, but there is evidence that its effect on 5-HT2A, D2, or D4 receptors may be important. Other aspects of the pharmacology of clozapine which may contribute to its actions include potent alpha 1-adrenergic, M1, M2, M3, and M5 receptor blocking properties, as well as M4 agonist effects.
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PMID:Role of serotonin in the action of atypical antipsychotic drugs. 758 21

At present, dopamine receptors are divided into two groups, dopamine D1-like receptors and dopamine D2-like receptors. In the study of these receptors, application of molecular biology methods has led to the identification of several structurally distinct subfamilies of receptors. D1-like subfamily contains D2, D3, and D4 receptors. These receptors are the primary targets in treatment of schizophrenia, Parkinson's disease and Huntington's chorea. Some of the neuroleptics have very selective action on certain subtypes of dopamine receptors, however, it seems that the efficient treatment of e.g. schizophrenia can be reached only by drugs which affect not only dopaminergic receptors but also 5-HT and possibly other receptors. It is of interest that the antipsychotic drugs originally led to the discovery of dopamine receptors and their subtypes and now, in turn, these receptors are used to search for more selective drugs with antipsychotic and antiparkinsonic effects.
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PMID:[Dopaminergic receptors--nomenclature and classification of types and subtypes]. 758 15

Conventional neuroleptics are widely accepted as being effective against the positive symptoms of schizophrenia, but do not benefit all patients. Furthermore, they are relatively ineffective against negative symptoms and cognitive disorders, and most have unpleasant side effect profiles. New strategies for treating schizophrenia include the development of dopamine antagonists with high selectivity for different subtypes of dopamine receptors, dopamine partial agonists, antagonists at different serotonin (5-hydroxytryptamine; 5-HT) receptor subtypes, drugs with mixed pharmacological profiles and drugs which modify transmission via amino acids or peptides in the brain. The prospect is that some of these strategies will lead to the introduction of new drugs and that some of these will become the standards against which future drugs will be compared. The search for new drugs and their use in clinical practice will also lead to developments in our knowledge and understanding of schizophrenia.
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PMID:New drugs for the treatment of schizophrenic patients. 760 35

Ritanserin (RIT), widely-used as a selective 5-HT2A/2C receptor antagonist, has been reported to produce significant therapeutic effects on the negative symptoms of schizophrenia and to improve extrapyramidal side effects induced by neuroleptics. Because midbrain dopamine (DA) systems are believed to be the major site of action for many antipsychotic drugs, the effect of RIT on substantia nigra DA neurons was examined in chloral hydrate-anesthetized rats using single unit recording techniques. Systemic injection of RIT (0.1-6.4 mg/kg, i.v.) had no consistent effect on basal firing rate but significantly reversed the inhibition induced by both direct and indirect DA agonists. However, our data suggest that this effect of RIT is largely mediated by a mechanism independent of 5-HT. Thus the 5-HT2A/2C agonist 1(2,5 dimethyoxy-4-iodophenyl)-2-aminopropane showed no effect on either basal firing rate or the inhibition induced by the direct DA agonist quinpirole. Neither the selective 5-HT2A antagonist MDL 100907 nor depletion of endogenous 5-HT using p-chlorophenylalanine mimicked the effect of RIT (i.e., attenuated quinpirole-induced inhibition). Furthermore, the effect of RIT persisted in animals pretreated with p-chlorophenylalanine. Because RIT is known to bind D2-like receptors and because the inhibition of DA neurons induced by low doses of a direct DA agonist is believed to be mediated by DA autoreceptors, these results suggest that RIT may act on DA autoreceptors directly as a DA antagonist. Since similar doses of RIT were reported to have no significant effect on postsynaptic D2 receptors in the striatum, it is possible that RIT at the doses used may selectively block DA autoreceptors.
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PMID:Ritanserin, a 5-HT2A/2C antagonist, reverses direct dopamine agonist-induced inhibition of midbrain dopamine neurons. 763 36

In vivo occupation of dopamine D1 and D2 and serotonin (5-HT)2 receptors by typical and atypical antipsychotic drugs (APD) was examined using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, which nonselectively and irreversibly inactivates these receptor sites. APD were classified as typical or atypical based on their capacity to induce extrapyramidal side effect in humans and/or catalepsy in laboratory rodents. Pretreatment of rats with typical APD (haloperidol, 0.25-3 mg/kg; chlorpromazine, 5-10 mg/kg; cis-flupenthixol, 1 mg/kg; zotepine, 5 mg/kg; nemonapride, 0.5-2 mg/kg) potently reversed the N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline-induced D2 receptor inactivation in rat striatum. In contrast, some atypical APD or its candidates (clozapine, 5-30 mg/kg; fluperlapine, 10 mg/kg; risperidone, 0.25-3 mg/kg; setoperone, 0.025-0.25 mg/kg; ORG 5222, 0.25 mg/kg) showed considerable occupation of 5-HT2 receptors in cerebral cortex with smaller or negligible occupation of D2 and D1 receptors. Pretreatment with the other atypical APD (sulpiride, 30 mg/kg; amperozide, 1 mg/kg) had no effect on these three receptors, although at higher doses, sulpiride (60 mg/kg) and amperozide (5 mg/kg) slightly but significantly reversed D2 and 5-HT2 receptor inactivation, respectively. It was concluded that a certain group of atypical APD is characterized by high occupancy of 5-HT2 receptor with lower or minimal occupancy of D2 and D1 receptors in vivo. The relevance of these characteristics of atypical APD was discussed in relation to extrapyramidal side effects and the therapeutic effects on schizophrenia.
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PMID:Dopamine D1, D2 and serotonin2 receptor occupation by typical and atypical antipsychotic drugs in vivo. 768 43

These studies explore the distribution of putative neuroactive peptides in the human olfactory bulb. Localization of synaptophysin-, serotonin-, cholecystokinin-, substance P-, and somatostatin-like staining was examined by immunocytochemical protocols. The results provide new insights into the composition and laminar segregation of subpopulations of neurons and neuronal processes in the human olfactory bulb. The prominent synaptophysin-like immunoreactivity observed in the glomeruli of the human olfactory bulb is consistent with the notion that the density of synapses, and hence the density of synaptic vesicles, is highest in the glomeruli. Serotonin-like immunoreactivity suggested a variable innervation of glomeruli ranging from a dense tangled ball of fibers within the glomerulus to a sparse innervation by a single immunoreactive fiber. There was no evidence of serotonin-like immunoreactive cell bodies in either the olfactory bulb proper, anterior olfactory nucleus, or proximal regions of the lateral olfactory tract. Cholecystokinin-like immunoreactivity was limited to fibers found largely in the juxtaglomerular region of the glomerular layer. In the deeper layers of the olfactory bulb, cholecystokinin-like immunoreactive fibers did not show any of branching or arborization that was evident in the juxtaglomerular region. Substance P-like immunoreactivity was seen in varicose fibers distributed in all of the human olfactory bulb laminae. In addition, stained multipolar neurons were found in the area of the anterior olfactory nucleus. Somatostatin-like immunoreactivity was similar to that of substance P in that a plexus of stained fibers was found in all laminae of the olfactory bulb. Also, somatostatin-like immunoreactive cell bodies were found in the area of the anterior olfactory nucleus. However, as compared to substance P, somatostatin had a less dense plexus of immunoreactive fibers in the olfactory bulb. These results increase our understanding of the fundamental organization of the human olfactory system. The current data, coupled with prior studies, provide a foundation from which to study the cellular pathology of diseases with known olfactory system sequelae such as Alzheimer's, Parkinson's, and schizophrenia.
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PMID:Immunohistochemical analyses of the human olfactory bulb. 769 Mar 71


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