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)

Synthetic substance P has been discovered to stimulate significantly the formation of dopa in the limbic, striatum, hemisphere and diencephalon regions of the brain and the lower brain stem. There was no effect upon 5-hydroxytryptophan formation or on tryptophan or tyrosine levels. After inhibition of monoamine synthesis by N'-(DL-SERYL)-N2-(2, 3, 4-trihydroxybenzyl)hydrazine, substance P significantly accelerated the disappearance of dopamine, noradrenaline and 5-hydroxytryptamine. Substance P appears to stimulate monoaminergic neurons in the brain and to serve as an excitatory transmitter in nerve terminals impinging upon dopaminergic cell bodies. A similar stimulation of noradrenaline and 5-hydroxytryptamine indicate a similar transmitter role for noradrenergic and serotonergic neurons. These data strengthen questions about the possible clinical influence of substance P in disease states involving monoaminergic mechanisms including Parkinsonism and schizophrenia.
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PMID:Effect of synthetic substance P on monoaminergic mechanisms in brain. 0 76

1 The roles of catecholamine and 5-hydroxytryptamine (5-HT) release in mediating backward walking and circling were studied in rats. 2 These behaviours occurred in animals given 15 mg/kg intraperitoneally of (+)-amphetamine (which predominantly releases catecholamines) or either p-chloroamphetamine or fenfluramine (which predominantly release 5-HT). They also occurred when smaller doses of (+)-amphetamine (5 mg/kg) and either p-chloroamphetamine (2--5 mg/kg) or fenfluramine (5 mg/kg) were given together. 3 Characteristic dopamine-dependent behaviours (rearing, licking, gnawing) resulting from (+)-amphetamine injection were greatly reduced by p-chloroamphetamine or fenfluramine. 4 Characteristic 5-HT-dependent behaviours (wet dog shake, hind limb abduction) resulting from injection of either p-chloroamphetamine or fenfluramine were unaffected by (+)-amphetamine. 5 Fragmentary backward walking and circling resulting from levallorphan injection (50 mg/kg s.c.) were decreased by (+)-amphetamine at low dosage. 6 Results in general strengthen previous evidence that backward walking and circling are mediated by simultaneous dopamine and 5-HT release. 7 The possible relevance of the above findings to hallucinogenic activity, amphetamine psychosis, schizophrenia and abnormal movements due to L-DOPA treatment is discussed.
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PMID:Backward walking and circling: behavioural responses induced by drug treatments which cause simultaneous release of catecholamines and 5-hydroxytryptamine. 46 94

The brains from 12 schizophrenic patients were investigated post-mortem for their content of noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT), homovanillic acid (HVA), and 5-hydroxyindolacetic acid (5-HIAA). Six of the schizophrenics had been lobotomized 25--30 years prior to death. A control group matched for age was collected in the autopsy room. The concentrations of NA, DA, and HVA in different parts of the brain from the schizophrenic group did not differ from those of the controls. 5-HT was determined in 11 nuclei or areas of the brain. The schizophrenic group had lower mean values compared with the controls, and in the hypothalamus, medulla oblongata, and hippocampus the difference was at a significant level. 5-HIAA was determined in six areas of the brain but only in a few cases. There was a trend towards lower means of 5-HIAA in the schizophrenics. Cause of death, medication, food intake, age, time between death and autopsy, time the corpses have lain in room temperature, and dissection technique are discussed in relation to these findings. These variables have to be kept under careful control before changes can be claimed as having pathogenetic importance for schizophrenia or for the progressing dementia in this disease.
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PMID:Monoamines and monoamine metabolites in brains from demented schizophrenics. 47 74

This study examined serotonin (5-hydroxytryptamine; 5HT) receptor responsivity in 22 chronic schizophrenic patients and 17 healthy control subjects. The 5HT agonist meta-chlorophenylpiperazine (MCPP) was used as a probe of serotonergic function. MCPP (0.35 mg/kg) or placebo was administered orally after a 3-week drug-free period in a randomized double-blind design. Hormonal (adrenocorticotropic hormone and prolactin), temperature, and behavioral responses and MCPP blood levels were assessed for 210 minutes after administration of the capsules. The schizophrenic patients had blunted temperature responses compared with those of the healthy control subjects: MCPP raised body temperature in the control subjects, but not in the patients. Behavioral responses also differed in the two groups: MCPP increased the total Brief Psychiatric Rating Scale (BPRS) score in the control subjects and tended to decrease it in the patients. In patients, MCPP decreased the BPRS psychosis subscore. Hormonal responses did not differ significantly in the two groups. These findings suggest that further exploration of 5HT function in schizophrenia is warranted.
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PMID:Serotonin function in schizophrenia: effects of meta-chlorophenylpiperazine in schizophrenic patients and healthy subjects. 133 94

It has been suggested that sigma receptor antagonists may be useful as antipsychotic drugs and that 5-hydroxytryptamine (5-HT2) receptor antagonists produce improvements of the negative symptoms of schizophrenia. [1-(Cyclopropylmethyl)-4-(2'-(4''-fluorophenyl)-2'- oxoethyl)-piperidine HBr] (DuP 734) is a novel compound with high affinity for the sigma (Ki = 10 nM) and 5-HT2 (Ki = 15 nM) receptors, but low affinity for dopamine receptors (Ki > 1000 nM) as well as 33 other receptors, ion channels and second messenger systems in vitro. DuP 734 did not inhibit the synaptosomal uptake of dopamine, 5-HT or norepinephrine. Oral administration of DuP 734 potently blocked 5-hydroxy-L-trytophan (5-HTP)-induced head twitch in the rat (ED50 = 6.5 mumol/kg), indicating 5-HT2 antagonist activity. Extracellular single-unit recording studies demonstrated that DuP 734 antagonized the effect of the selective sigma ligand (+)-3-(3-hydroxyphenyl-N-(1-propyl) piperidine [(+)-3-PPP] on dopamine neuronal activity in the substantia nigra of the rat with an ED90 of 3.6 mumol/kg i.v. The sigma receptor agonists (+)-SKF 10,047 and phencyclidine both elicited rotational behavior in rats with unilateral lesion of the substantia nigra. The rotational behavior induced by either (+)-SKF 10,047 or phencyclidine was dose-dependently antagonized by DuP 734 with oral ED50 of 8.7 and 19.6 mumol/kg, respectively. The 5-HT2 receptor antagonist ICI 169,369, even at high doses (up to 33 mumol/kg, s.c.), did not antagonize the rotational behavior induced by (+)-SKF 10,047.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:DuP 734 [1-(cyclopropylmethyl)-4-(2'(4''-fluorophenyl)-2'-oxoethyl)- piperidine HBr], a sigma and 5-hydroxytryptamine2 receptor antagonist: receptor-binding, electrophysiological and neuropharmacological profiles. 136 72

Ondansetron hydrochloride dihydrate is a 5-hydroxytryptamine (5-HT3) antagonist that was recently approved by the Food and Drug Administration for the treatment of chemotherapy-induced emesis. The mechanism of action is thought to be due to competitive inhibition of specific serotonin receptors in the central nervous system and gastrointestinal tract. In clinical trials with cisplatin-induced emesis, ondansetron resulted in complete control of vomiting (0-2 episodes) in 55-87% of patients during the first 24 hours of chemotherapy administration. It was significantly more effective than metoclopramide in comparative trials. Ondansetron is also being investigated for the treatment of radiation- and anesthesia-associated nausea and vomiting. Studies in animals demonstrate potential efficacy in the treatment of anxiety, drug withdrawal, and schizophrenia. The drug is generally well tolerated, with no reported extrapyramidal reactions.
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PMID:Parenteral ondansetron for the treatment of chemotherapy- and radiation-induced nausea and vomiting. 153 80

Evidence is reviewed that 5-HT (5-hydroxytryptamine, serotonin) acting through the 5-HT3 receptor subtype can influence behaviour relevant to anxiety, schizophrenia and cognitive disorders, and that 5-HT3 receptor antagonists such as ondansetron (CAS 116002-70-1) can correct behavioural disturbance in the absence of effect on normal behaviour. The 5-HT3 receptor antagonists exert a breadth of action over a wide dose range in rodent and primate models to inhibit aversive behaviour in animal models of anxiety and certain symptoms of withdrawal from drugs of abuse, alcohol, nicotine, diazepam and cocaine, to antagonise increased locomotor activity caused by mesolimbic dopamine excess, and facilitate performance in cognitive tests. The studies reveal an important role for 5-HT3 receptors in the regulation of limbic-cortical functioning, and a critical role for 5-HT3 receptor antagonists to establish the role of 5-HT3 receptors in schizophrenia, anxiety, drug withdrawal phenomena and cognitive disturbance. Preliminary clinical trials indicate a positive effect of ondansetron in anxiety, schizophrenia, alcohol withdrawal and age associated memory impairment.
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PMID:Serotonin and psychiatric disorders. A key to new therapeutic approaches. 158 95

8B-N-cyclohexyl-6-methyl-1(1-methylethyl)ergoline-8-carboxamide (LY237733) is an ergoline with potent and highly selective 5-hydroxytryptamine (5-HT) antagonist activity. The in vitro radioligand displacement studies showed that LY237733 has a preferential affinity for 5-HT1c and 5-HT2 receptors compared to other monoaminergic receptors. This characteristic is shared with other previously described ergoline 5-HT antagonists, such as LY53857 and sergolexole. In parallel ligand displacement assays, LY237733 had a similar potency to sergolexole. LY237733 was equipotent to sergolexole, but slightly less potent than LY53857 in the antagonism of 5-HT-induced elevation in blood pressure and quipazine-induced elevation in corticosterone levels, which are considered to be measures of 5-HT2 and possibly 5-HT1c antagonist activity. LY237733 failed to antagonize pergolide or 8-hydroxy-2-(di-n-propylamino)tetralin-induced elevations in serum corticosterone levels, indicating selectivity for the 5-HT1c/2 receptor, relative to 5-HT1a and D2 dopaminergic receptors. The only in vivo response that could be detected after administration of LY237733 alone in doses less than 1 mg/kg was the amplification of male rat sexual behavior. LY237733 was 10 to 100 times more potent than LY53857 or sergolexole in augmenting sexual responses of male rats with different levels of sexual response capacity. LY237733 has a much longer serum half-life than sergolexole. These studies have provided the pre-clinical rationale to evaluate the effects of this compound in the treatment of sexual disorders such as psychogenic erectile dysfunction, and other therapeutic indications for a 5-HT2 antagonist, including depression, anxiety, schizophrenia and migraine.
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PMID:Preclinical studies on LY237733, a potent and selective serotonergic antagonist. 173 Oct 51

In a neuroendocrine challenge paradigm, the present study investigated responses of schizophrenic patients to m-chlorophenylpiperazine (MCPP), a serotonin (5-hydroxytryptamine, 5HT) agonist. In an oral dose of 0.25 mg/kg, MCPP was administered in a placebo-controlled double-blind design to male schizophrenic patients (n = 7) and normal male controls (n = 8). Behavioral (Positive and Negative Syndrome Scale; PANSS) and hormonal (cortisol, prolactin) variables were measured over the subsequent 210 min. The schizophrenic patients experienced an overall exacerbation of psychopathology on MCPP as compared with placebo (p less than 0.05), with specific worsening of PANSS-positive symptoms (p less than 0.025) and PANSS activation (p less than 0.001). In addition, the schizophrenic patients showed significantly lower cortisol (p less than 0.05) and prolactin (p less than 0.05) responses than the normal subjects. The schizophrenic patients had lower peak MCPP blood levels than the normal subjects, although this difference was not statistically significant. The findings are discussed in terms of 5HT receptor(s) sensitivity and the pharmacokinetics of MCPP in schizophrenia.
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PMID:The MCPP challenge test in schizophrenia: hormonal and behavioral responses. 175 20

1. Genetic databases are an expanding and readily accessible repository of information on the mapping and sequencing of the human genome, and that of other model organisms. The integration and application of this information to neuropsychiatric disease is illustrated using neuroendocrine and neuropharmacologic data, computerized and other genetic databases. 2. This computer-assisted integrated approach to knowledge structures permits the rapid generation of hypotheses, the prompt identification of candidate gene loci, an explanation for genetic heterogeneity, and strategies for the use of potential linked markers. 3. Results using this integrated search strategy demonstrate that over 30 candidate loci for neuropsychiatric disease have currently been mapped in man (spread over 14 chromosomes in the human genome), and that at least 6 homologous loci have been mapped in mouse. 4. Using a metabolic pathway approach, it can be shown that the best current candidate gene locus for a subtype of schizophrenia located on chromosome 5q11-13 (HGML10 # SCZD1 and OMIM #181510) is in the serotonergic pathway, i.e. a receptor for 5-hydroxytryptamine (subtype 1A; HGML10 #HTR1A) which also maps in the same chromosomal region. 5. Parallels are suggested between inborn errors of metabolic pathways in the somatic endocrine system (using insulin-dependent diabetes mellitus as a paradigm) and the neurotransmitter and hormonal systems within the brain. 6. A subset of neuropsychiatric disorders may thus be viewed as inborn errors of cerebral metabolic pathways primarily affecting the biogenic amine pathways.
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PMID:Integrated genetic databases in the study of neuropsychiatric diseases: inborn errors of cerebral metabolic pathways? 187 20


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